Clearance & Elimination detail explanation.pptx

Drug elimination & clearance

Drug elimination Drug elimination refers to “Irreversible removal of drug from the body by all routes of elimination .” The declining plasma drug concentration observed after systemic drug absorption shows that the drug is being eliminated from the body but does not indicate which elimination processes are involved . Major eliminating organs: Kidney & Liver

KIDNEY LIVER

Drug excretion Drug excretion is “ R emoval of the intact drug ” Nonvolatile drugs are excreted mainly by renal excretion, a process in which the drug passes through the kidney to the bladder and ultimately into the urine. Volatile drugs , such as gaseous anesthetics, alcohol, or drugs with high volatility, are excreted via the lungs into expired air . Other pathways for drug excretion may include the excretion of drug into bile, sweat, saliva, milk (via lactation), or other body fluids.

Drug metabolism Biotransformation or drug metabolism is “the process by which the drug is chemically converted in the body to a metabolite.” Biotransformation is usually an enzymatic process. A few drugs may also be changed chemically by a non-enzymatic process (eg, ester hydrolysis). The enzymes involved in the biotransformation of drugs are located mainly in the liver. Other tissues such as kidney, lung, small intestine, and skin also contain biotransformation enzymes.

contents DRUG CLEARANCE Introduction and mechanism Models Determination of Clearance Relationship of clearance with half life and volume of distribution ELIMINATION OF DRUGS Hepatic elimination (Percent of Drug Metabolized, Drug Biotransformation reactions, (Phase-I reactions and phase-II reactions), First pass effect, Hepatic clearance of protein bound drugs and Biliary excretion of drugs .) Renal excretion ( Renal clearance, Tubular Secretion and Tubular Reabsorption .) Elimination of drugs through other organs (Pulmonary excretion, Salivary excretion, Mammary excretion, Skin excretion and Genital excretion .)

Drug elimination

Drug elimination is described in terms of clearance from a well stirred compartment containing uniform drug distribution Clearance may be defined as the volume of the fluid cleared of drug from the body per unit of time The term clearance describes the process of drug elimination from the body or from a single organ without identifying the individual processes involved . Units for clearance  ml/min or L/hr

WHY STUDY ELIMINATION & CLEARANCE????

Drug elimination

Renal drug excretion

Renal drug excretion Major route of elimination for many drugs Drugs that are NON VOLATILE, WATER SOLUBLE , have a LOW MOLECULAR WEIGHT or are SLOWLY BIOTRANSFORMED BY THE LIVER are eliminated by renal excretion The processes by which a drug is excreted via the kidneys may include any combination of the following: Glomerular filtration Active tubular secretion Tubular reabsorption

GF and ATS tends to increase the concentration of drugs in lumen and hence facilitate excretion whereas TR decreases it and prevents the movement of drug out of the body. Thus, rate of excretion can be given as: Rate of excretion = Rate of filtration + Rate of secretion – Rate of reabsorption

Glomerular filtration Is a unidirectional process It occurs for most small molecules (MW< 500) including undissociated (unionized) and dissociated (ionized) drugs. Protein bound drugs behave as large molecules and do not get filtered at the glomerulus The major driving force for glomerular filtration is the hydrostatic pressure within the glomerular capillaries The kidneys receive a large blood supply (approx. 25% of the cardiac output) via the renal artery, with very little decrease in the hydrostatic pressure.

Glomerular filtration rate(GFR) “ it estimates that how much blood passes through the glomeruli each minute ” It is measured by using a drug that is eliminated by filtration only ( ie , the drug is neither reabsorbed nor secreted) Examples of such drugs are inulin and creatinine Therefore, the clearance of inulin = GFR , which is equal to 125-130 mL/min

Glomerular filtration rate(GFR) Glomerular filtration of drugs is directly related to the free or nonprotein-bound drug conc. in the plasma As the free drug conc . in the plasma increases , the glomerular filtration for the drug increases proportionately, thus increasing renal drug clearance for some drugs Glomerular filtration rate (GFR) is a test used to check how well the kidneys are working.

Active tubular secretion Is an active transport process Active renal secretion is a carrier mediated system that requires energy input, b/c the drug is transported against a conc. gradient The carrier system is capacity limited and may be saturated Drugs with similar structures may compete for the same carrier system Two active renal secretion systems have been identified, systems for Weak acids (Organic anion transporter OAT) Weak bases (Organic cation transporter OCT ) Example : Probenecid competes with penicillin for the same carrier system (weak acids)

Active tubular secretion rate is dependent on renal plasma flow Drugs commonly used to measure active tubular secretion:  p-amino- hipuric acid (PAH) and iodopyracet (diodrast) For a drug that is excreted solely by glomerular filtration , the elimination half life may change markedly in accordance with the binding affinity of the drug for plasma proteins In contrast, drug protein binding has very little effect on the elimination half life of the drug excreted mostly by active secretion (b/c drug protein binding is reversible, drug bound to plasma protein rapidly dissociates as free drug is secreted by the kidneys) Example : some of the penicillins are extensively protein bound, but their elimination half lives are short due to rapid elimination by active secretion.

Tubular reabsorption Occurs after the drug is filtered through the glomerulus and can be an active or a passive process If a drug is completely reabsorbed (eg, glucose), then the value for the clearance of the drug is approximately zero . For drugs that are partially reabsorbed, clearance values are less than the GFR of 125-130 mL/min Many drugs are weak acids or bases, therefore the pH of the filtrate can greatly influence the extent of reabsorption for many drugs. The reabsorption of drugs that are acids or weak bases is influenced by the pH of the fluid in the renal tubule ( ie , urine pH ) and the pKa of the drug

Both of these factors together determine the percentage of dissociated (ionized) and undissociated (nonionized) drug. Generally, the undissociated species is: more lipid soluble (less water soluble) has greater membrane permeability, and hence easily reabsorbed from the renal tubule back into the body. This process of drug reabsorption can significantly reduce the amount of drug excreted, depending on the PH of the urinary fluid and the pKa of the drug. The pKa of the drug is a constant, but the normal urinary pH may vary from 4.5-8 depending on diet, pathophysiology and drug intake

By far the most important changes in urinary pH are caused by fluids administered intravenously( i.e. solutions of bicarbonate or ammonium chloride) Excretion of these solutions may drastically change urinary pH and alter drug reabsorption and drug excretion by the kidney The percentage of ionization of weak acid drug can be determined by Handerson-Hasselbalch equation.

Where, [ A – ] are the concentrations of the ionized form of the acid, [HA] is the concentration of the unionized form, and vice versa

For weak acids pH= pKa + log Rearranging the above equation gives: = 10 pH-pKa OR [ionized]= 10 pH-pKa [unionized] As we know, % of drug ionized= Putting the value of [ionized] in above equation gives:

% of drug ionized= = % of drug ionized=

Similarly for weak bases: pH= pKa+ log OR

For example : Amphetamine It is a weak base , will be reabsorbed if urine pH is made alkaline and more lipid soluble nonionized species are formed. In contrast, acidification of urine will cause the amphetamine to become more ionized(form a salt). The salt form is more water soluble, less likely to be absorbed, and tends to be excreted into the urine more quickly. For example : Salicylic acid It is a weak acids , acidification of the urine causes greater reabsorption of the drug and alkalinization of the urine causes more rapid excretion of the drug. Hence weakly basic drugs will be reabsorbed rapidly if urine is made alkaline and weakly acidic drugs will be reabsorbed rapidly if urine is made acidic.

Calculation of urine plasma ratio From the Handerson-Hasselbalch Eq. a conc. ratio for the distribution of a weak acid or basic drug b/w urine and plasma may be derived. For weak acids For weak bases

To summarize , renal drug excretion is a composite of passive filtration at the glomerulus, active secretion in the proximal tubule and Passive/active reabsorption in the distal tubule.

Factors affecting renal drug excretion Molecular Weight (pc property of drug) Urine pH GFR Lipid solubility (pc property of drug) Protein binding Pathological condition Concurrent drug administration A ge

1) MOLECULAR WT. Drugs having mol.wt . less than or equal to 300 dalton are excreted by kidneys While those having mol. Wt. b/w 300-500 are eliminated by both kidneys and bile 2) URINE pH One of the most important factor affecting renal drug excretion Acidification of urine promotes the reabsorption of weak acids(as being in unionized form) While promotes the excretion of weak bases as they are ionized in acidic medium & ionized drug is more water soluble & will be excreted more & vice versa

3) G.F.R. If the glomerular filtration rate is high then excretion of drugs which are excreted via glomerular filtration will be more but in case of low GFR in disease conditions or due to any other reason will decrease the rate of drug excretion 4) LIPID SOLUBILITY Lipid soluble drugs are not excreted and remain in circulation while water soluble drugs are much more rapidly excreted

5) PROTEIN BINDING P rotein bound drugs cannot cross glomerular capillaries & hence excretion of protein bound drugs cannot occur through this process However tubular secretion process of renal excretion does not depend upon protein binding and protein bound drugs can be excreted via tubular secretion b/c protein binding is reversible and active secretion breaks the protein bound drugs 6) PATHOLOGICAL CONDITION If renal function is impaired in case of disease then there is decreased in elimination rate of drugs that usually undergo renal excretion i.e. streptomycin, gentamicin

7) CONCURRENT DRUG ADMINISTRATION Affects renal drug excretion of already administered drug eg probenecid vs penecillin 8) AGE In case of old age as renal function is impaired so elimination of drug which are eliminated by kidney is also impaired To determine Excretion, following parameters are used: Clearance Elimination half life Elimination rate constant

Renal clearance Before moving to Renal Clearance, we must know what is Clearance ????

clearance Also known as systemic clearance or total body clearance It is defined as: volume of blood which is completely cleared of drug per unit time . Clearance is the measure of the functional ability of substance to be removed by eliminating organ. Clearance is pharmacokinetic term measuring drug elimination from the body without identifying the mechanism or process involved Clearance considers the entire body as a single drug eliminating system from which many unidentified elimination process may occur UNITS Volume/time (liters/hour; milliliters/minute), ml/min/kg, L/hr/kg

If the drug has more than 1 route of elimination then, total clearance is the sum of individual clearances: CL T = CL renal + CL hepatic + CL n OR CL T = CL renal + CL non-renal

Basic formulas to determine clearance: Total clearance = Cl T = -------- where, DE= amount of drug excreted, dDE / dt = drug elimination rate 1

Drugs are usually eliminated from the body at rate which is proportional to their plasma concentration . As 1 st order elimination rate ( dD E / dt ) is equal to total drug in body ( kD B ), hence dD E / dt = kD B as, D B = Vd* C p dD E / dt =k VdC p

If we put the value of elimination rate in eq.1, we get ClT = --------- Where , K = overall elimination rate constant ( K = ke+ km) Vd = volume of distribution 2

This Equation shows that clearance is the product of k and Vd , both of which are constants. As the plasma drug concentration decreases during elimination, the rate of drug elimination decrease accordingly, but clearance remains constant. Clearance is constant as long as rate of drug elimination is a 1 st order process. Clearance values are often normalized on a per kilogram body weight basis, such as milliliters/minute per Kilogram. The clearance for an individual patient is estimated as the product of the clearance per kilogram multiplied by the body weight( Kg) of the patient.

Example : In case of Penicillin …. Plasma drug concentration (g/ml) Elimination rate ( ug /min) Clearance (ml/min) 2 30 15 10 150 15

As the elimination rate constant (k ) represents the sum total of all the rate constant for drug elimination, including excretion and biotransformation, Cl T is the sum total of all the clearance processes in the body, including clearance through kidney (renal clearance), lungs, and liver(hepatic clearance). Renal Clearance = k e V D Lung Clearance = K l V D Hepatic Clearance = Km VD Therefore, Body Clearance = k e V D + K l V D + K m V D OR Body Clearance = (Ke + Kl + Km) VD = K VD

ClEARANCE MODELS Compartment model Physiological model Non-compartmental or Model independent approach

c a b

COMPARTMENT MODEL The calculation of clearance from k and Vd assumes a defined model . Clearance is commonly used to describe 1 st order drug elimination from compartment model such as the one compartment model in which the distribution volume and elimination rate constants are well defined. Total clearance = Cl T = -------- where, D E = amount of drug excreted, dD E / dt = drug elimination rate 1 a

As 1 st order elimination rate ( dD E / dt ) is equal to total drug in body ( kD B ), hence dD E / dt = kD B as, D B = Vd * C p dD E / dt =k VdC p If we put the value of elimination rate in eq.1, we get Body Clearance= Cl T = k . Vd

Physiological /Organ drug clearance Clearance may be calculated for any organ involved in the irreversible removal of drug from the body. Physiological pharmacokinetic models are based on drug clearance through individual organs or tissue groups . For any organ, Clearance may be defined as the fraction of blood volume containing drug that flows through organ and eliminated of drug per unit time. From definition, organ drug clearance is the product of the blood flow ( Q ) to the organ and the extraction ratio ( ER , the fraction of drug excreted by the organ as drug passes through ). Cl = Q(ER) ------ ( i ) b

If the drug concentration in the blood ( Ca ) entering the organ is greater than the drug concentration of blood ( Cv ) leaving the organ ,then some of the drug has been extracted by the organ. The ER is given as: ER = -------- (ii) ER is a ratio with NO units . Values of ER range from 0-1 An ER of 0.25 indicates that 25% of the incoming drug conc. is removed by the organ as the drug passes through it.

Substituting for ER into equation ( i ) Cl = Q ( ) ------- (iii) The physiologic approach to clearance shows that clearance depends on the blood flow rate and the ability of the organ to eliminate drug. However clearance measurements using the physiological approach require invasive techniques to obtain measurement of blood flow and extraction ratio. Mostly applied in case of hepatic clearance .

Model-Independent Method Model independent methods are non compartment model approaches used to calculate certain pharmacokinetic parameters such as clearance and bioavailability (F). The major advantage of model independent approach is that no assumption for a specific compartment model is required to analyze data. NO need to calculate k and Vd. In model independent approach, plasma level time curve is used for calculation of clearance. c

For example : According to this approach, the total body clearance is estimated by Cl T = Where, D o = initial dose and [AUC] o ∞ = o ∫ ∞ C p dt Because [AUC] o ∞ is calculated from the plasma drug conc.-time curve from 0 to infinity using the trapezoidal rule, no compartmental model is assumed. This calculation of Cl T is referred to as a non-compartment or model-independent method.

Renal drug clearance Renal clearance (Cl R ) is defined as: “ the volume of plasma that is cleared of drug per unit time through kidney. ”

More simply, it is defined as urinary excretion rate ( dDu / dt ) divided by plasma concentration (Cp) Cl R = =

For any drug cleared through the kidney: rate of drug passing through kidney = rate of drug excreted in urine i.e. Cl R . Cp = Qu . Cu Cl R = Qu . Where, Qu = rate of urine flow Cu = concentration of drug in urine Also, Cl R = Qu . = =

Comparison of drug excretion methods (via kidney) From a physiologic viewpoint, however, renal clearance may be considered as the ratio of the sum of the Glomerular filtration and active secretion rates less the reabsorption rate divided by the plasma drug conc entration Renal Clearance =

Clearance ratio Mechanism of excretion < 1 Drug partially reabsorbed = 1 Drug filtered only > 1 Drug actively secreted Clearance ratio Mechanism of excretion Drug partially reabsorbed Drug filtered only Drug actively secreted In order to understand that through which process the drug undergoes renal clearance, the ratio of renal clearance of drug to that of inulin i.e. Clearance ratio is taken .

FILTERATION ONLY If glomerular filtration is the sole process for drug excretion and no drug is reabsorbed, then amount of drug filtered at any time ,t, will always be: Cp . GFR If the Cl R of the drug is by glomerular filtration only , then: Cl R = GFR Otherwise, Cl R represents all the process by which drug is cleared through the kidney, including any combination of filtration, reabsorption and active secretion.

If we compare the rate of drug excretion using a compartment approach and physiological approach, we get: or Clr = ke Vd or = ke dDu / dt = ke . Vd . Cp dDu / dt = Clr . Cp ke Vd . Cp = Clr . Cp Above equation shows that , in the absence of other processes of drug elimination, the excretion rate constant reflects the volume pumped out per unit time due to GFR relative to the volume of body compartment VD.

For a drug with reabsorption fraction of ‘ Fr ’ the drug excretion rate is reduced and equation is given as: dDu / dt = Clr (1-Fr) Cp FILTERATION & REABSORPTION

FILTRATION AND ACTIVE SECRETION For a drug that is primarily filtered and secreted, with negligible reabsorption, the overall excretion rate will exceed GFR. At low drug plasma concentration, active secretion is not saturated and drug is excreted by filtration and active secretion. At high concentrations, the percentage of drug excreted by active secretion decreases due to saturation.

DETERMINATION OF RENAL CLEARANCE 1. Graphical determination of Clr : The clearance is given by the slope of the curve obtained by plotting the rate of drug excretion in urine ( dDu / dt ) against Cp . For a drug that is excreted rapidly : ( dDu / dt ) is large, the slope is steeper. For a drug that is excreted slowly through the kidney: the slope is smaller. Plasma level (Cp) Rate of drug excretion ( dDu /dt) Higher Cl Lower Cl

From equation, Cl R = …………….. (1) Multiplying both sides by Cp Cl R . Cp = 𝑑𝐷𝑢/ 𝑑𝑡 ………. (2) By rearranging equation (2) and integrating o ∫ D u dD u = Cl R o ∫ t Cp dt [D u ] o t = Cl R [AUC] o t

A graph is then plotted of cumulative drug excreted in the urine ( [ D u ] o t ) versus the area under the concentration – time curve ( [AUC] o t ) Renal clearance is obtained from the slope of the curve. The area under curve can be estimated by the trapezoidal rule. Disadvantage : if a data point is missing, the cumulative amount of drug excreted in the urine is difficult to obtain. However, if the data are complete then the determination of clearance is more accurate by this method.

2. M odel-independent methods Clearance rates may also be estimated by a single (nonographical) calculation from [AUC]o- ∞ and the total amount of drug excreted in the urine, D u ∞ . Cl T = Do/[AUC]o- ∞ If the total amount of drug excreted in the urine, Du ∞ , has been obtained, then renal clearance is calculated by Cl R =

Clearance can also be calculated from fitted parameters. ( i.e. compartment model approach ) If the volume of distribution and elimination constants are known, body clearance ( Cl T ), renal clearance ( Cl R ), and hepatic clearance ( Cl h ) can be calculated according to the following expressions: Cl T = kV D ( i ) Cl R = k e V D (ii) Cl h = k m V D (iii)

Total body clearance ( Cl T ) is equal to the sum of renal clearance and hepatic clearance i.e. Cl T = Cl R + Cl h (iv) By substitution equations ( i ) and (ii) into equation (iv), kV D = k e V D + k m V D (v) Dividing by V D on the both sides of equation (v), we get K= k e + k m (vi)

RENAL CLEARANCE OF PROTEIN BOUND DRUG Clearance of protein bound drugs ONLY occurs by active tubular secretion and not by Glomerular filtration. Thus the relation; Clr = n eeds modification i.e. in place of Cp, we should use ONLY unbound fraction of drug. Clr = However, for most drug studies, the total plasma drug concentration is used in clearance calculations

Relationship of clearance to elimination half life & volume of distribution The half life of a drug can be determined if the clearance and V D are known. We know Cl T = kV D (1) as, K = 0.693/t 1/2 Putting value in eq.1 Cl T = 0.693V D /t 1/2 t 1/2 =

Thus, from above equation as Cl decreases (which might happen in some renal diseases), t 1/2 for the drug increases . Total body clearance , Cl T is a more useful index of measurement of drug removal as compared to the elimination half life t 1/2 . Total body clearance , Cl T takes into account changes in both the apparent vol. of distribution, V D and the t 1/2 .

Total body clearance of drug after intravenous infusion When drugs are administered by IV infusion, the total body clearance is obtained with the following equation. Cl T = Where; C ss is the steady state plasma drug concentration and R is the rate of infusion.

So….. The elimination of most drugs from the body involves the process of both metabolism (biotransformation) and renal excretion . For many drugs, the principal site of metabolism is the liver . Drugs that are highly metabolized(such as phenytoin) often demonstrate large inter subject variability in the elimination half lives and are dependent on the intrinsic activity of the biotransformation enzymes, which may vary by genetic and environmental factors.

Inter subject variability in elimination half lives is less for drugs that are eliminated primarily by renal drug excretion . Renal drug excretion is highly dependent on GFR and blood flow to the kidney. Since GFR is relatively constant among individuals with normal renal function, the elimination of drugs that are primarily excreted unchanged in the urine is also less variable.

Hepatic clearance

Hepatic clearance ‘Volume of blood perfuses the liver and is cleared of drug per unit time’ Hepatic clearance ( Clh ) is also equal to total body clearance ( ClT ) minus renal clearance ( ClR ) as follows : Clh = ClT - ClR -------- If blood flow ( Q ) and extraction ratio ( ER ) are determinable, then hepatic clearance can be calculated as: Cl h = Q . ER -------- Where, Q = blood flow to liver, ER = extraction ratio= Ca- Cv /Ca Ca = conc. of drug in artery, Cv = conc. of drug in vein 1 2

If ER=1 : then the rate limiting step in hepatic clearance is the hepatic blood flow , and hepatic clearance is almost equal to the hepatic blood flow. i.e. Cl h = Q In above case, Cl h is less affected by fraction of drug protein binding. In contrast, if ER is very less : then Cl h is affected by drug protein binding and the intrinsic activity of liver to eliminate the drug. (as only unbound fraction of drug is capable of permeation) and is not affected by hepatic blood flow.

If intrinsic clearance ( Clint ) and fraction unbound in plasma ( fu ) are known, then hepatic clearance can be calculated as: Cl h = Cl int . F u Intrinsic clearance: It is the ability of liver to remove drug from blood in the absence of confounding factors (blood flow, drug-protein binding) It can be calculated by the ratio of Michales-Menten parameters : Cl int = = max. velocity of metabolic reaction = ½ = conc. of drug which shows ½ reaction -------- 3

% of drug metabolized Because these rates of elimination at low drug concentration are considered first-order processes, the percentage of total drug metabolized may be obtained by the following expression: Similarly, in case of renal excretion : Km = Metabolism rate constant Ke = Excretion rate constant K= elimination rate constant

Fraction of Drug Excreted Unchanged ( fe ) & Fraction of Drug Metabolized ( 1- fe ) For many drugs, the literature has approximate values for the fraction of drug ( f e ) excreted unchanged in the urine For most drugs, the fraction of dose eliminated unchanged ( fe ) and the fraction of dose eliminated as metabolites (1-fe) can be determined using formulas: 4 --------

Solve me The total body clearance of a drug is 10 mL/ min/kg. The renal clearance is not known. From a urinary drug excretion study, 60% of the drug is recovered intact and 40% is recovered as metabolites. What is the hepatic clearance for the drug, assuming that metabolism occurs in the liver?

answer Hepatic clearance = total body clearance × (1 – fe ) (12.7) where f e = fraction of intact drug recovered in the urine. Hepatic clearance = 10 × (1 – 0.6) = 4 mL/min/kg In this example, the metabolites are recovered completely and hepatic clearance may be calculated as total body clearance times the percent of dose recovered as metabolites. Often, the metabolites are not completely recovered, thus precluding the accuracy of this approach.

Extrahepatic Metabolism A few drugs (eg, nitroglycerin) are metabolized extensively outside the liver. This is known as extrahepatic metabolism . A simple way to assess extrahepatic metabolism is to calculate hepatic (metabolic) and renal clearance of the drug and compare these clearances to total body clearance.

Solve me Morphine clearance, Cl T , for a 75-kg male patient is 1800 mL/min. After an oral dose, 4% of the drug is excreted unchanged in the urine ( f e = 0.04). The fraction of drug absorbed after an oral dose of morphine sulfate is 24% ( F = 0.24). Hepatic blood flow is about 1500 mL/min. Does morphine have any extrahepatic metabolism?

answer Since f e = 0.04 nonrenal clearance Cl nr = (1 – 0.04) Cl T = 0.96 Cl T . Therefore, Cl nr = 0.96 × 1800 mL/min = 1728 mL/ min. Since hepatic blood flow is about 1500 mL/ min, the drug appears to be metabolized faster than the rate of hepatic blood flow. Thus, at least some of the drug must be metabolized outside the liver. The low fraction of drug absorbed after an oral dose indicates that much of the drug is metabolized before reaching the systemic circulation

FIRST PASS EFFECT For some drugs, the route of administration affects the metabolic rate of the compound. For example, a drug given parenterally, transdermally , or by inhalation may distribute within the body prior to metabolism by the liver. In contrast, drugs given orally are normally absorbed in the duodenal segment of the small intestine and transported via the mesenteric vessels to the hepatic portal vein and then to the liver before entering the systemic circulation. Drugs that are highly metabolized by the liver or by the intestinal mucosal cells demonstrate poor systemic availability when given orally.

FIRST PASS EFFECT The rapid metabolism of an orally administered drug prior to reaching the systemic circulation is known as first pass effect or presystemic elimination . Or Enzymatic degradation of orally administered drug prior reaching to systemic circulation is called first pass effect .

Sites : - Liver The liver is the most important site of pre-systemic elimination because of: Its high level of drug metabolizing enzyme Its ability to rapidly metabolize many different kinds of drug molecules Its anatomic location and blood supply Drugs undergoing first pass metabolism: Β -blockers : E.g . propranolol, metoprolol Analgesics : E.g . meperidine, propoxyphene Antidepressants : E.g . imipramine, nor- tryptyline Antiarrythmics : E.g . Lidocaine, verapamil

Evidence of first pass metabolism …. When there is lack of parent drug in the systemic circulation, first pass effect is suspected …. The evidence for this is provided by: AUC In case of first pass metabolism, AUC for orally administered drug is less than the AUC for IV administered drug. 2) From experimental findings in animals, first-pass effects may be assumed if the intact drug appears in a cannulated hepatic portal vein but not in general circulation. S ampling of drug from the hepatic portal vein and artery is difficult and performed mainly in animals only. For an orally administered drug that is chemically stable in the gastrointestinal tract and is 100% systemically absorbed ( F = 1), the area under the plasma drug concentration curve, AUC 0.oral should be the same when the same drug dose is given intravenously, AUC 0.IV . 3 ) Absolute Bioavailability ( F) It also indicates the degree of first pass effect undergone by drugs F = [ AUC]PO/ DosePO [AUC]IV/ DoseIV

For drugs undergoing first pass effect the value of F is less than 1 and AUC oral < AUC IV. Eg, nitroglycerine, morphine and propranolol. 4) Liver extraction ratio (E.R) It is the estimate of the extent to which a drug is removed by the liver after oral administration Liver E.R = Ca- Cv /Ca Where, Ca = drug conc. entering the liver i.e. in arteries Cv = drug conc. leaving the liver i.e. in veins Drugs with low ER have lower 1 st pass effect after oral administration

Liver Extraction Ratio Because there are many other reasons for a drug to have a reduced F value, the extent of first-pass effects is not precisely measured from the F value. The liver extraction ratio (ER) provides a direct measurement of drug removal from the liver after oral administration of a drug. E.R = Ca- Cv /Ca Ca = drug conc. entering the liver i.e. in arteries Cv = drug conc. leaving the liver i.e. in veins Because C a is usually greater than C v , ER is usually less than 1. For example, for propranolol, ER or [ E ] is about 0.7 ie , about 70% of the drug is actually removed by the liver before it is available for general distribution to the body.

Liver Extraction Ratio By contrast, if the drug is injected intravenously, most of the drug would be distributed before reaching the liver, and less of the drug would be metabolized the first time the drug reaches the liver . The ER may vary from 0 to 1.0. An ER of 0.25 means that 25% of the drug is removed by the liver. If both the ER for the liver and the blood flow to the liver are known, then hepatic clearance, Cl h , may be calculated by the following expression : Cl h = Q . ER = Q (Ca – Cv ) / Ca

Methods to overcome first pass effect Change the route of administration i.e. avoid oral route e.g. Nitroglycerine sublingually, xylocaine may be given parenterally to avoid the first-pass effects. Administer in large doses Change to rapidly absorbable dosage form

Significance of first pass effect Pro-drugs are generally inactive unless they are converted into their parent compounds by metabolism e.g . Becampicillin  A mpicillin Many anticancer drugs are first converted to their active metabolite and then exert their action e.g. cyclophosphamide & isophosphamide 5-flurouracil Decreased concentration of parent drug in systemic circulation Decreased therapeutic response of the drug Dose adjustment

Relationship between Absolute Bioavailability and Liver Extraction The following relationship between bioavailability and liver extraction enables a rough estimate of the extent of liver extraction: F = 1 - ER - F ″ where F is the fraction of bioavailable drug ER is the drug fraction extracted by the liver F ″ is the fraction of drug removed by nonhepatic process prior to reaching the circulation. If F ″ is assumed to be negligible ie , there is no loss of drug due to chemical degradation, gut metabolism, and incomplete absorption, ER may be estimated from: F = 1 – ER

Relationship between Absolute Bioavailability and Liver Extraction Substituting the formula of F in the above equation we get:- ER is a rough estimation of liver extraction for a drug. Many other factors may alter this estimation: the size of the dose , the formulation of the drug, and the pathophysiologic condition of the patient all may affect the ER value obtained . if an oral drug product has slow dissolution characteristics or release rate, then more of the drug will be subject to first-pass effect compared to doses of drug given in a more bioavailable form. Liver ER provides valuable information in determining the oral dose of a drug when the intravenous dose is known. For example, propranolol requires a much higher oral dose compared to an IV dose to produce equivalent therapeutic blood levels, because of oral drug extraction by the liver. L iver extraction is affected by blood flow to the liver.

Estimation of Reduced Bioavailability Due to Liver Metabolism and Variable Blood Flow Blood flow to the liver plays an important role in the amount of drug metabolized after oral administration. Changes in blood flow to the liver may substantially alter the percentage of drug metabolized and therefore alter the percentage of bioavailable drug . The relationship between blood flow, hepatic clearance, and percent of drug bioavailable is: Cl h is the hepatic clearance of the drug Q is the effective hepatic blood flow F ′ is the bioavailability factor obtained from estimates of liver blood flow and hepatic clearance, ER . This equation provides a reasonable approach for evaluating the reduced bioavailability due to first-pass effect. The usual effective hepatic blood flow is 1.5 L/min, but it may vary from 1 to 2 L/min depending on diet, food intake, physical activity, or drug intake

Estimation of Reduced Bioavailability Due to Liver Metabolism and Variable Blood Flow Presystemic elimination or first-pass effect is a very important consideration for drugs that have a high extraction ratio . Drugs with high presystemic elimination tend to demonstrate more variability in drug bioavailability between and within individuals. The quantity and quality of the metabolites formed may vary according to the route of drug administration, which may be clinically important if one or more of the metabolites has pharmacologic or toxic activity. Drugs with low extraction ratios, such as theophylline, have very little presystemic elimination .

Relationship between Blood Flow, Intrinsic Clearance, and Hepatic Clearance F actors that affect the hepatic clearance of a drug include :- Blood flow to the liver Intrinsic clearance Fraction of drug bound to plasma protein

Blood flow to the liver A change in liver blood flow may alter hepatic clearance and F ′. A large blood flow may deliver enough drug to the liver to alter the rate of metabolism. In contrast, a small blood flow may decrease the delivery of drug to the liver and become the rate-limiting step for metabolism. The hepatic clearance of a drug is usually calculated from plasma drug data rather than whole-blood data. Hepatic clearance can be calculated by equation Cl h = Q . ER Where, Q= blood flow to liver ER= extraction ratio= Ca- Cv /Ca Ca= conc. of drug in artery Cv = conc. of drug in vein This indicates that clearance is directly proportional to blood flow

High extraction ratio drugs For some drugs such as isoproterenol , lidocaine and nitroglycerine the extraction ratio is high (>0.7) and drug is removed by the liver almost as rapidly as the organ is perfused For drugs with very high extraction ratios, the rate of drug metabolism is sensitive to changes in hepatic blood flow. Thus, an increase in blood flow to the liver will increase the rate of drug removal by the organ. Propranolol , a beta-blocker decreases the hepatic blood flow by decreasing cardiac output and thus decreases its own clearance through the liver.

INTRINSIC CLEARANCE It is used to describe the total ability of the liver to metabolize the drug in the absence of flow limitation reflecting the inherent activities of the mixed function oxidases and all other enzymes. Intrinsic clearance is a distinct characteristic of a particular drug. Intrinsic clearance may be shown to be analogous to the ratio V max / K M for a drug that follows Michaelis – Menten kinetics. Hepatic clearance is a concept for characterizing drug elimination based on both the blood flow and the intrinsic clearance of the liver as shown below: Cl h = Q .

Low extraction ratio drugs Hepatic clearance changes with blood flow and the intrinsic clearance . Hepatic clearance of drugs with low extraction ratio are more affected by the intrinsic activity of mixed function oxidases than the hepatic blood flow e.g. theophylline, phenylbutazone and procainamide C learance to be estimated when physiologic or disease conditions cause changes in blood flow or intrinsic enzyme activity. Smoking, for example, can increase the intrinsic clearance for the metabolism of many drugs. Changes or alterations in mixed-function oxidase activity or biliary secretion can affect the intrinsic clearance and thus the rate of drug removal by the liver. Drugs that show low extraction ratios and are eliminated primarily by metabolism demonstrate marked variation in overall elimination half-lives within a given population .

Low extraction ratio drugs For example, the elimination half-life of theophylline varies from 3 to 9 hours. This variation in t ½ is thought to be due to genetic differences in intrinsic hepatic enzyme activity . Moreover, the elimination half-lives of these same drugs are also affected by enzyme induction , enzyme inhibition , age of the individual, nutritional, and pathologic factors. Clearance may also be expressed as the rate of drug removal divided by plasma drug concentration T he rate of drug removal by the liver is usually the rate of drug metabolism

Hepatic clearance of protein bound drugs: restrictive and non restrictive clearance from binding They are assumed to be of two types: Restrictively cleared drug: A lso known as binding sensitive Extraction ratio is less B ound drugs are not able to diffuse through cell membrane & thus not able to reach the site of metabolism, while free (unbound) drugs can reach the site of MFOs and are subjected to metabolism . For restrictively cleared drugs, change in binding generally alters drug clearance T hus for such drugs increase in free drug concentration in the blood will make more drug available for hepatic extraction . Most drugs are restrictively cleared. E xample , diazepam, quinidine, tolbutamide , and warfarin . The clearance of these drugs is proportional to the fraction of unbound drug ( f u ).

Hepatic clearance of protein bound drugs: restrictive and non restrictive clearance from binding Non restrictively eliminated drugs: Examples are propranolol , morphine, and verapamil. These are extracted by the liver regardless of drug bound to protein or free . A drug is nonrestrictively cleared if its hepatic extraction ratio (ER) is greater than the fraction of free drug ( f u ) , and the rate of drug clearance is unchanged when the drug is displaced from binding. The protein binding of a drug is a reversible process and for a nonrestrictively bound drug, the free drug gets “stripped” from the protein relatively easily compared to a restrictively bound drug during the process of drug metabolism The elimination half-life of a nonrestrictively cleared drug is not significantly affected by a change in the degree of protein binding .

Hepatic clearance of protein bound drugs: restrictive and non restrictive clearance from binding For a drug with restrictive clearance, the relationship of blood flow follows Clh =Q . f u is the fraction of drug unbound in the blood and Cl’ int is the intrinsic clearance of free drug . When Cl’int is very small in comparison to hepatic blood flow then above equation reduces to Cl h = Q . Or Cl h = fu.Cl’int A change in Cl’ int or f u will cause a proportional change in Cl h for drugs with protein binding.

Hepatic clearance of protein bound drugs: restrictive and non restrictive clearance from binding For a drug having very high Cl’int , in comparison to flow i.e. Cl’int >>Q, the equation becomes Cl h = Q . i.e. Cl h =Q Thus for drugs with a very high Clint= Clh depends on hepatic blood flow and independent of protein binding.

Drug biotransformation reactions The hepatic biotransformation enzymes play an important role in the inactivation and subsequent elimination of drugs that are not easily cleared through the kidney. For most biotransformation reactions, the metabolite of the drug is more polar than the parent compound. This enables the drug to be eliminated more quickly . A lipid-soluble drug crosses cell membranes and is easily reabsorbed by the renal tubular cells, exhibiting a consequent tendency to remain in the body. In contrast, the more polar metabolite does not cross cell membranes easily, is filtered through the glomerulus, is not readily reabsorbed, and is more rapidly excreted in the urine.

Drug biotransformation reactions T he nature of the drug and the route of administration may influence the type of drug metabolite formed. For example, isoproterenol given orally forms a sulfate conjugate in the gastrointestinal mucosal cells, whereas after IV administration, it forms the 3- O -methylated metabolite via S - adenosylmethionine and catechol- O - methyltransferase . Azo drugs such as sulfasalazine are poorly absorbed after oral administration. However, the azo group of sulfasalazine is cleaved by the intestinal microflora, producing 5-aminosalicylic acid and sulfapyridine , which is absorbed in the lower bowel. The biotransformation may be classified according to the pharmacologic activity of the metabolite or according to the biochemical mechanism for each biotransformation reaction. For most drugs, biotransformation results in the formation of a more polar metabolite(s) that is pharmacologically inactive and is eliminated more rapidly than the parent drug.

Drug biotransformation reactions The metabolite may be pharmacologically active or produce toxic e ffects. Prodrugs are inactive and must be biotransformed in the body to metabolites that have pharmacologic activity. Prodrugs are designed to improve drug stability , increase systemic drug absorption , or to prolong the duration of activity . For example, the antiparkinsonian agent levodopa crosses the blood–brain barrier and is then decarboxylated in the brain to l-dopamine, an active neurotransmitter. l-Dopamine does not easily penetrate the blood–brain barrier into the brain and therefore cannot be used as a therapeutic agent

SITES OF BIOTRANSFORMATION Liver The primary site for metabolism of almost all drugs because it is relatively rich in a large variety of metabolizing enzymes . Metabolism by organs other than liver ( called as extra-hepatic metabolism ) is of lesser importance because lower level of metabolizing enzymes is present in such tissues. Within a given cell, most drug metabolizing activity is found in the smooth endoplasmic reticulum, SER and the cytoso l. Drug metabolism can also occur in mitochondria, nuclear envelope and plasma membrane . A few drugs are also metabolized by non-enzymatic means called as non-enzymatic metabolism . For example, atracurium, (a neuromuscular blocking drug)

Other SITES OF BIOTRANSFORMATION..CONT. Cutaneous tissues Epidermis can carry out several metabolic reaction including glucuronide conjugation There are evidences of cutaneous metabolism of adrenal steroids, hydrocortisone and flurouracil Vidarabine (an antiviral agent) has cutaneous metabolism. First pass drug metabolism in skin reduces the duration and potency of locally applied drugs

Gastrointestinal tract Drugs can be conjugated by various enzymes in intestinal epithelium and consequently this presystemic metabolism cause an incomplete bioavailability of drugs. Presystemic metabolism of premarin in gastrointestinal tract is example. Lungs Lung are perfused by entire blood supply and the drug in blood is presented to enzymes in lungs for metabolism A few drugs are prone to be metabolized in lungs.

Kidneys Some drugs are converted to their metabolites in kidney by the action of angiotensin convertase enzyme(ACE ). Brain A few drugs are metabolized in brain e.g. Levodopa is converted into dopamine (active form)

Sub-cellular Locations of Metabolizing Enzymes 1. ENDOPLASMIC RETICULUM (microsomes ): the primary location for the metabolizing enzymes. (a) Phase I: cytochrome P450 , flavin-containing monooxygenase, aldehydeoxidase, carboxylesterase, epoxide hydrolase, prostaglandin synthase, esterase. (b) Phase II: uridine diphosphate-glucuronosyltransferase, glutathione S-transferase, amino acid conjugating enzymes. 2. CYTOSOL (the soluble fraction of the cytoplasm): many water-soluble enzymes. (a) Phase I: alcohol dehydrogenase, aldehyde reductase, aldehyde dehydrogenase, epoxide hydrolase, esterase. (b) Phase II : sulfotransferase, glutathione S-transferase, N-acetyl transferase, catechol 0-methyl transferase, amino acid conjugating enzymes.

3. MITOCHONDRIA . (power house of the cell ; generates ATP) ( a) Phase I: monoamine oxidase, aldehyde dehydrogenase, cytochrome P450. (b) Phase II: N-acetyl transferase, amino acid conjugating enzymes. 4. LYSOSOMES . Phase I: peptidase. 5. NUCLEUS . Phase II: uridine diphosphate-glucuronosyltransferase (nuclear membrane of enterocytes).

A number of enzymes in animals are capable of metabolizing drugs. These enzymes are located mainly in the liver , but may also be present in other organs like lungs, kidneys, intestine, brain, plasma, etc. Majority of drugs are acted upon by relatively non-specific enzy mes, which are directed to types of molecules rather than to specific drugs. The drug metabolizing enzymes can be broadly divided into two groups: Microsomal enzymes N on-microsomal enzymes. DRUG METABOLIZING ENZYMES

Microsomal enzymes : The endoplasmic reticulum (especially smooth endoplasmic reticulum) of liver and other tissues contain a large variety of enzymes, together called microsomal enzymes ( microsomes are minute spherical vesicles derived from endoplasmic reticulum after disruption of cells by centrifugation, enzymes present in microsomes are called microsomal enzymes). They catalyze glucuronide conjugation , most oxidative reactions , and some reductive and hydrolytic reactions. The monooxygenases , glucuronyl transferase , etc are important microsomal enzymes.

Non-microsomal enzymes : Enzymes occurring in organelles/sites other than endoplasmic reticulum (microsomes) are called non-microsomal enzymes. These are usually present in the cytoplasm, mitochondria, etc. and occur mainly in the liver, Gl tract, plasma and other tissues. They are usually non-specific enzymes that catalyse few oxidative reactions, a number of reductive and hydrolytic reactions, and all conjugative reactions other than glucuronidation . None of the non-microsomal enzymes involved in drug biotransformation is known to be practical.

Hepatic microsomal enzymes (oxidation, conjugation) Extrahepatic microsomal enzymes (oxidation, conjugation) Hepatic non-microsomal enzymes (acetylation, sulfation,GSH, alcohol/aldehyde dehydrogenase, hydrolysis, ox/red) DRUG METABOLISM

HEPATIC BIOTRANSFORMATION It is the conversion of a drug to its metabolites. These metabolites can be inactive, active having activity as their parent drug or having different activities. The metabolites are more excretable from the body. The pathway of drug biotransformation is divided into two major groups of reactions : 1 Phase I metabolism ( asynthetic reactions ) 2 Phase II metabolism ( synthetic reactions ) A drug may be exposed to both of the reactions mentioned above and their consequences may be illustrated as following.

prodrug Active drug Polar metabolite Renal or biliary excretion Phase I reactions Active metabolites Inactive metabolites Phase II reactions Conjugated derivatives Renal or biliary excretion

PHASE I METABOLIC REACTIONS Also known as non-synthetic reactions or functionalization reactions Phase I reactions usually occur first and involve a change in drug molecule by non-synthetic reactions such as: Oxidation Reduction Hydrolysis

SIGNIFICANCE In these reactions, a functional group is either introduced or exposed on the drug molecule so as it can be attacked by phase II enzymes. Group induction or exposure on a molecule in phase I reactions lead to the increased polarity . The resulting product of phase I reaction is susceptible to phase II reactions.

PHASE-I METABOLIC REACTIONS For example, oxygen is introduced into the phenyl group on phenylbutazone by aromatic hydroxylation to form oxyphenbutazone , a more polar metabolite . Codeine is demethylated to form morphine. T he hydrolysis of esters , such as aspirin or benzocaine, yields more polar products, such as salicylic acid and p - aminobenzoic acid, respectively For some compounds, such as acetaminophen, benzo[a] pyrene , and other drugs containing aromatic rings, reactive intermediates , such as epoxides, are formed during the hydroxylation reaction. These aromatic epoxides are highly reactive and will react with macromolecules, possibly causing liver necrosis (acetaminophen) or cancer (benzo[a] pyrene ). S alicylic acid is also conjugated directly (phase II reaction) without a preceding phase I reaction .

PHASE I REACTIONS includes…. OXIDATION : Oxidative reactions are most important metabolic reactions , as energy in animals is derived by oxidative combustion of organic molecules containing carbon and hydrogen atoms. The oxidative reactions are important for drugs because they increase hydrophilicity of drugs by introducing polar functional groups such as -OH.

The most important group of oxidative enzymes are microsomal mono oxygenases or mixed function oxidases (MFO). These enzymes are located mainly in the hepatic endoplasmic reticulum (ER ) and require both molecular oxygen (0 2 ) and NADPH to effect the chemical reaction. Mixed function oxidase name was proposed in order to characterise the mixed function of the oxygen molecule, which is essentially required by a number of enzymes located in the microsomes.

The term monooxygenses for the enzymes was proposed as they incorporate only one atom of molecular oxygen into the organic substrate with concomitant reduction of the second oxygen atom to water. The most important component of mixed function oxidases is the cytochrome P-450 because it binds to the substrate and activates oxygen. The wide distribution of cytochrome P-450 containing MFOs in varying organs makes it the most important group of enzymes involved in the biotransformation of drugs.

The several oxidation reactions occurring in body are: 1. Oxidation of alkyl chain: Alkyl compounds, or alkyl side chains of the aromatic drugs with carboxyl, aldehyde or amino group undergo oxidation. Examples include : CH3-CH2-OH CH2-C-OH CH2-COOH

2. Oxidation of aromatic ring NH-CO-CH3 OH NH-CO-CH3 Acetanilide Acetaminophen oxidation

Nitrosobenzene Oxidation Aniline NH2 3. N-oxidation NO2

4. Sulfoxidation S N CH3 CH3 CH2-CH2-CH2-N S N CH3 CH3 CH2-CH2-CH2-N O Chlorpromazine Chlorpromazine sulfoxide oxidation

5. Oxidative deamination N CH2-CH2-NH2 N CH2-C-OH O oxidation 5-OH Tryptamine 5-OH Indolacetic acid OH OH

6. Oxidative dealkylation NH-CO-CH3 O-CH-CH3 oxidation NH-CO-CH3 OH Phenacetin P-Acetaminophenol

Both Microsomal as well as non-microsomal enzymes are involved in oxidation reactions. Hydroxylation of aromatic ring, aliphatic hydroxylation,N-oxidaton and sulfoxidation are the reactions catalysed by microsomal enzymes . Whereas, dehydrogenation of ethyl alcohol into acetaldehyde, conversion of hypoxanthine to xanthine, xanthine to uric acid and tyrosine to dopa are catalysed by nonmicrosomal oxidases .

REDUCTION : Reduction is less common than the oxidation and occurs in both, microsomal as well as in nonmicrosomal metabolizing systems These include: 1. N-Reduction NO 2 NH 2 nitrobenzene aniline

2. Ketone reduction CO.CH 3 CH 2 OH Acetophenone 1 Phenyl ethanol

CO-O-CH 2 -CH 2 -N C 2 H 5 C 2 H 5 NH 2 OH-CH 2 -CH 2 -N C 2 H 5 C 2 H 5 NH 2 COOH + Procaine Para-amino benzoic acid Diethylaminoethanol HYDROLYSIS : Also referred to as the replacement reaction and is indicated by enzyme esterases and amidases . The examples of hydrolysis are : Ester hydrolysis: It yields alcohol and acid

2. Amide hydrolysis:- It yields amine and acid C- NH 2 O COOH + NH3 Benzamide Benzoic acid

(Conjugation) PHASE II REACTIONS Once a polar constituent is revealed or placed into the molecule, a phase II or conjugation reaction may occur. Common examples include the conjugation of salicyclic acid with glycine to form salicyluric acid or glucuronic acid to form salicylglucuronide . Phase II, synthetic or conjugation reactions may occur with the drug molecules with exposed or induced polar constituent as a consequence of Phase I reactions The phase II reactions offer a mechanism whereby a functional group of a drug can be blocked by addition of a conjugating agent . Since the outcome of such processes are generally products with increased molecular size (and altered physicochemical properties) they are also called as synthetic reactions The conjugation reactions use conjugating reagents that are derived from the compounds involved in carbohydrate, lipid, fat or protein metabolisms. The conjugating agents available for such reactions include Glucuronic acid, sulfate, glycine, acetylCoA, glutathione.

(Conjugation) PHASE II REACTIONS Quite often, a phase I reaction may not yield a metabolite that is sufficiently hydrophilic or pharmacologically inert but conjugation reactions generally result in products with total loss of pharmacologic activity and high polarity . Hence , phase II reactions are better known as true detoxification reactions . Since these reactions generally involve transfer of moieties to the substrate to be conjugated, the enzymes responsible are called as transferases .

(Conjugation) PHASE II REACTIONS Some of the conjugation reactions may have limited capacity at high drug concentrations , leading to nonlinear drug metabolism . In most cases, enzyme activity follows first-order kinetics with low drug (substrate) concentrations. At high doses, the drug concentration may rise above the Michaelis – Menten rate constant ( K M), and the reaction rate approaches zero order ( V max ). Glucuronidation reactions have a high capacity and may demonstrate nonlinear (saturation) kinetics at very high drug concentrations. In contrast, glycine, sulfate, and glutathione conjugations show lesser capacity and demonstrate nonlinear kinetics at therapeutic drug concentrations. The limited capacity of certain conjugation pathways may be due to several factors, including (1) limited amount of the conjugate transferase (2 ) limited ability to synthesize the active nucleotide intermediate (3 ) limited amount of conjugating agent , such as glycine

Glucuronidation and sulfate conjugation are very common phase II reactions that result in water-soluble metabolites rapidly excreted in bile and or urine. Acetylation and mercapturic acid synthesis are conjugation reactions that are often implicated in the toxicity of drugs. Two schemes have been proposed for the phase II reactions. In scheme A , the conjugating agent, activated with energy combines with the drug molecule in the presence of an appropriate drug transferase enzyme to form the conjugate. In scheme B , a drug may be activated to a high energy compound to react with a conjugating agent in the presence of the conjugating agent transferase enzyme The schemes A and B, with examples can be illustrated in the following figure:

Phase 2 reactions includes… Glucuronidation Sulfate conjugation Acetylation Methylation Amino acid conjugation Glutathione and m ercaptopuric acid conjugation

The following are the phase II reactions along with examples: 1. Glucuronidation : Glucuronic acid conjugation is one of the most common route of drug metabolism. Its significance lies in readily available supply of Glucuronic acid in liver The glucuronoid conjugates are pharmacologically inactive The reaction involves the condensation of drug with the activated form of Glucuronic acid i.e. uridine diphosphate Glucuronic acid This reaction is catalyzed by glucuronyl transferase in liver

Glucuronidation occurs for the drugs containing functional groups OH , NH2 , SH and COOH These reactions include: O- Glucuronidation Occurs by ester linkages with carboxylic acids Occurs by ether linkages with phenols and alcohols Alcohol + glucuronide ether o glucuronide

N- glucuronidation : Occurs with amines (mainly aromatic ) Occurs with amides and sulfonamides + Glucuronide NH2 NH-C6H9O6 Aniline N-glucuronide

2. Sulfate conjugation The sulfate conjugation occurs in the drugs with functional groups of OH and NH2 . The high energy form of sulfate is 3’phosphoadenosin 5’ phosphosulfate (PAPS) O-SO2-OH OH Phenol Phenyl sulfuric acid

3. Acetylation Acetylation occurs in the drugs with OH or NH groups Acetyl CoA is the high energy form of the conjugating agent Acetylated product is usually less polar than the parent drug and precipitate in sufficient concentration in kidney tubules causing kidney damage and crystaluria . The less polar metabolite is reabsorbed in the renal tubule and has a longer elimination half-life . For example, procainamide (t ½ = 3 to 4 hours) has an acetylated metabolite, N - acetylprocainamide , which is biologically active and has an t ½ of 6-7 hour. T he N -acetyltransferase enzyme responsible for catalyzing the acetylation of isoniazid and other drugs demonstrates a genetic polymorphism. Two distinct subpopulations have been observed to inactivate isoniazid, including the “ slow inactivators ” and the “rapid inactivators ”. T he former group may demonstrate an adverse effect of isoniazid, such as peripheral neuritis, due to the longer elimination half-life and accumulation of the drug. Acetylation is a conjugation reaction often implicated in the toxicity of the drug The drug metabolized by acetylation include sulfanilamide, sulfadiazine, procainamide and sulfisoxazole .

3. M ethylation The conjugating agent in methylation is CH3 from S- adenosylmethionine (SAM) The functional group combined with this conjugating agents are OH and NH2 Nicotinamide N-methyl nicotinamide

4. Amino acid conjugation The amino acid conjugation uses the glycine as a conjugating agent The high energy form of this conjugating agent is the Coenzyme A thioesters In amino acid conjugation, the glycine combines with the drugs having functional group COOH . The glycine conjugates are known as hippurates

5. Glutathione and Mercaptopuric acid conjugation Glutathione (GSH )- a tripeptide of glutamyl -cysteine-glycine that is involved in many important biochemical reactions. GSH is important in the detoxification of reactive oxygen intermediates into nonreactive metabolites and is the main intracellular molecule for protection of the cell. Through the nucleophilic sulfhydryl group of the cysteine residue, GSH reacts nonenzymatically and enzymatically via the enzyme glutathione S -transferase , with reactive electrophilic oxygen intermediates of certain drugs. The resulting GSH conjugates are precursors for a group of drug conjugates known as mercapturic acid ( N - acetylcysteine ) derivatives. The enzymatic formation of GSH conjugates is saturable . High doses of drugs such as acetaminophen may form electrophilic intermediates and deplete GSH in the cell. These intermediate bind covalently to hepatic cellular macromolecules, resulting in cellular injury and necrosis. The suggested antidote for intoxication (overdose) of acetaminophen is the administration of N - acetylcysteine ( Mucomyst ), a drug molecule that contains available sulfhydryl (R–SH) groups.

Metabolism of Enantiomers Many drugs are given as mixtures of stereoisomers. Each isomeric form may have different pharmacologic actions and different side effects . For example, the natural thyroid hormone is l -thyroxine, whereas the synthetic d enantiomer, d -thyroxine, lowers cholesterol but does not stimulate basal metabolic rate like the l form. Since enzymes as well as drug receptors demonstrate stereoselectivity , isomers of drugs may show differences in biotransformation and pharmacokinetics. With improved techniques for isolating mixtures of enantiomers, many drugs are now available as pure enantiomers. The rate of drug metabolism and the extent of drug protein binding are often different for each stereoisomer . (S)-(+) disopyramide is more highly bound in humans than (R )-(–) disopyramide .

Regioselectivity B iotransformation enzymes may be regioselective . In this case, the enzymes catalyze a reaction that is specific for a particular region in the drug molecule. For example, isoproterenol is methylated via catechol- O - methyltransferase and S - adenosylmethionine primarily in the meta position , resulting in a 3- O -methylated metabolite. Very little methylation occurs at the hydroxyl group in the para position

Genetic Variation of Cytochrome P-450 (CYP) Isozymes The most important enzymes accounting for variation in phase I metabolism of drugs is the cytochrome P-450 enzyme group, which exists in many forms among individuals because of genetic differences. Initially , the cytochrome P-450 enzymes were identified according to the substrate that was biotransformed . More recently, the genes encoding many of these enzymes have been identified. Multiforms of cytochrome P-450 are referred to as isozymes , and are classified into families (originally denoted by Roman numerals: I, II, III, etc ) and subfamilies (denoted by A, B, C, etc ) based on the similarity of the amino acid sequences of the isozymes. If an isozyme amino acid sequence is 60% similar or more, it is placed within a family. Within the family, isozymes with amino acid sequences of 70% or more similarity are placed into a subfamily, and an Arabic number follows for further classification. The individual gene is denoted by an Arabic number (last number) after the subfamily . A new nomenclature starts with CYP as the root denoting cytochrome P-450, and an Arabic number now replaces the Roman numeral.

Genetic Variation of Cytochrome P-450 (CYP) Isozymes The CYP3A subfamily of CYP3 appears to be responsible for the metabolism of a large number of structurally diverse endogenous agents (eg, testosterone, cortisol, progesterone, estradiol) and xenobiotics (eg, nifedipine , lovastatin, midazolam, terfenadine , erythromycin ). These are also involved in the metabolism of vindesine , vinblastine, and other vinca alkaloids. The substrate specificities of the P-450 enzymes appear to be due to the nature of the amino acid residues, the size of the amino acid side chain, and the polarity and charge of the amino acids. C ytochrome P-450 1A2 (CYP1A2) is involved in the oxidation of caffeine and CYP2D6 (P-450IID6 ) is involved in the oxidation of drugs, such as codeine, propranolol, and dextromethorphan. It is responsible for debrisoquine metabolism which is polymorphic in the population, with some individuals having extensive metabolism (EM) and other individuals having poor metabolism (PM ). Other drugs metabolized are flecainide , imipramine , and other cyclic antidepressants that undergo ring hydroxylation.

Genetic Variation of Cytochrome P-450 (CYP) Isozymes There are now at least eight families of cytochrome isozymes known in humans and animals. CYP 1–3 are best known for metabolizing clinically useful drugs in humans. Variation in isozyme distribution and content in the hepatocytes may affect intrinsic hepatic clearance of a drug. The levels and activities of the cytochrome P-450 isozymes differ among individuals as a result of genetic and environmental factors.

bioactivation Generally biotransformation or metabolism produces more water soluble chemical species and hence increase excretion. Thus toxicity is reduced. Bioactivation reactions are defined as biotransformation reactions which lead to products with higher toxicity/activity than the parent compounds. Reactive compounds generated may be wither:- Electrophiles (+):- these are deficient in electron pair and react with nucleophilic groups in macromolecules such as DNA and proteins. Or radicals (-) :- they contain odd number of electrons. Free radicals produce toxicity by peroxidation . Protection against free radicals is done by membrane structures neutralization by glutathione, antioxidants ,eg, vitamin A,E,C and enzymatic inactivation of free radicals.

CHRONOPHARMACOKINETICS AND TIME-DEPENDENT PHARMACOKINETICS Chronopharmacokinetics broadly refers to a temporal change in the rate process (such as absorption or elimination) of a drug. The temporal changes in drug absorption or elimination can be cyclical over a constant period (eg, 24-hour interval), or they may be noncyclical , in which drug absorption or elimination changes over a longer period of time . Time-dependent pharmacokinetics generally refers to a noncyclical change in the drug absorption or drug elimination rate process over a period of time. Time-dependent pharmacokinetics leads to nonlinear pharmacokinetics . T ime-dependent pharmacokinetics may be the result of alteration in the physiology or biochemistry in an organ or a region in the body that influences drug disposition. Time-dependent pharmacokinetics may be due to autoinduction or autoinhibition of biotransformation enzymes.

FACTORS AFFECTING BIOTRANSFORMATION (Kulkarni pg - 122-125)

TYPES OF FACTORS 1. Physicochemical properties of the drug 2. Chemical factors a. Induction of drug metabolizing enzymes b. Inhibition of drug metabolizing enzymes c. Environmental chemicals

TYPES OF FACTORS 3. Biological factors: a. A ge b. G ender c. G enetics d. R ace c. Diet f . Altered physiologic factors: i . Pregnancy ii. Hormonal imbalance iii. Disease states g. Temporal (time related) factor

1. Physicochemical properties of the drug Just as the absorption and distribution of a drug are influenced by drugs physicochemical properties, so is its interaction with the drug metabolizing enzymes . Molecular size and shape , pKa , acidity/basicity , lipophilicity and electronic characteristics of a drug influence its interaction with the active sites of enzymes and the biotransformation processes to which it is subjected. However , such an interrelationship is not clearly understood.

2. Chemical Factors a. Induction of drug metabolizing enzymes or enzyme induction b. Inhibition of drug metabolizing enzymes or enzyme inhibition c. Environmental chemicals

a) Enzyme Induction The phenomenon of increased drug metabolizing ability of the enzymes (especially of microsomal monooxygenase system) by several drugs and chemicals is called as enzyme induction and the agents which bring about such an effect are known as inducers . Mechanism involved in enzyme induction may be increased enzyme synthesis , decreased rate of enzyme degradation, enzyme stabilization enzyme activation . Eg, alcohol, barbiturates, phenytoin, rifampin etc Auto induction/ self induction: The phenomenon in which a drug induces their own metabolism. E.g. carbamazepine- antiepileptic . Enzyme induction results in decreased pharmacologic activity of most drugs and increased activity where the metabolites are active .

b) Enzyme Inhibition Decrease in the drug metabolizing ability of enzymes . It can be of the following types:- Competitive inhibition:- drugs compete with natural substrate for active site of an enzyme due to structural similarity. It is reversible. Eg, succinylcholine inhibits acetylcholine esterase by competing with acetylcholine. Non competitive inhibition:- inhibitors are structurally not related to natural substrates. Eg, enzyme inhibition by heavy metals. Repression:- may be caused because of decreases synthesis or increased degradation of enzyme. Enzyme inhibition generally results in prolonged pharmacologic action of a drug .

c) Environmental Chemicals Several environmental agents influence the drug metabolizing ability of enzymes. Aromatic hydrocarbon contained in Cigarette smokers act as enzyme inducers . Chronic alcoholism might lead to enzyme induction as well. Pesticides or Organophosphate insecticides may act as enzyme inducers . At high altitude decreased biotransformation occurs due to decreased oxygen leading to decreased oxidation of drugs .

3. Biological Factors

a ) AGE Age dependent differences are due to differences in enzyme content, enzyme activity and hemodynamics. In infants: M icrosomal enzyme system is not fully developed. The rate of metabolism is very low. Chloramphenicol does not have great efficacy in infants. Toxic effects in the form of grey baby syndrome might occur due to accumulation of chloramphenicaol . Shock and even death might occur if toxic levels get accumulated .

In elderly, most processes slow down which leads to decreased metabolism. Decrease in liver functions and decreased blood flow through the liver is common. All these factors decrease the metabolism. The drug doses should be decreased in the elderly

GENDER Gender related differences in the rate of metabolism are due to genetic control due to hormonal influence. These are due to differences in enzyme concentration, activities and changes in lipid environment of enzymes. Male have a higher BMR as compared to the females, thus can metabolize drugs more efficiently, e.g . salicylates and others might include ethanol , propanolol , benzodiazepines . b )

c) GENETIC differences Differences among strains within the same species is also known. A study of intersubject variability in drug response (due to differences in, for example , rate of biotransformation) is called as pharmacogenetics . Hence, drugs behave differently in different individuals due to genetic variations Succinyl choline , which is a skeletal muscle relaxant, is metabolized by pseudocholine esterase . Some people lack this enzyme, due to which lack of metabolism of succinyl choline might occur.

RACE/ SPECIES Asians, Blacks and Whites might have different drug metabolizing capacity. Examples include difference in drug metabolizing capacity of certain anti malarial . Ethnic variation is the difference observed in metabolism of drug among different races due to polymorphism . In most European countries, approx. 40 % population is fast acetylators and 96% of eskimos are fast acetylators Laboratory animals can metabolize drugs faster than man e.g. barbiturates. d)

DIET The enzyme content and activity is altered by a number of dietary components . Low protein diet decreases and high protein content in diet increases the drug metabolizing ability. Dietary deficiency of vitamins and minerals retard the metabolic activity of enzymes. e )

ALTERED PHYSIOLOGIC FACTORS f )

PREGNANCY During pregnancy, metabolism of some drugs is increased while that of others is decreased due to the presence of steroid hormones e.g. Phenytoin Phenobarbitone Pethidine

HORMONAL IMBALANCE Higher levels of one hormone may inhibit the activity of few enzymes while inducing that of others. E.g. Antipyrine half-life shortened in case of hyperthyroidism and prolonged during hypothyroidism

DISEASE STATES Liver disease such as hepatic carcinoma, cirrhosis, hepatitis, obstructive jaundice etc reduce the hepatic drug metabolizing ability and thus increase the half lives of almost all drugs. In renal diseases conjugation of salicylates , oxidation of vitamin D and hydrolysis of Procaine are impaired . Cardiovascular diseases , although have no direct effect, decrease the blood flow, which may slow down biotransformation of drugs like isoniazid, morphine and propanolol. Pulmonary conditions may decrease biotransformation. Procaine and procainamide hydrolysis is impaired.

TEMPORAL FACTOR Diurnal variations and variations in enzyme activity with light cycle is circadian rhythm . The study of variations in drug response as influenced by time is called as chronopharmacology . Time dependent change in drug kinetics is known as chronokinetics . Enzyme action is maximum during early morning and minimum in late afternoon which is probably due to high and low levels of coticosterone . Drugs such as aminopyrine , hexobarbital and imipramine showed diurnal variations in rats . g )

ROUTE OF ADMINISTRATION Oral route can result in extensive hepatic metabolism of some drugs (first pass effect). Lignocaine is almost completely metabolized if taken by oral route therefore the preferable route is Topical.

Biliary excretion of drugs Irreversible transfer of drug or drug metabolites from the plasma to the bile through the hepatocytes is called biliary excretion or biliary clearance Anatomy:- The intrahepatic bile ducts join outside the liver to form the common hepatic duct . The hepatic duct, containing hepatic bile, joins the cystic duct that drains the gallbladder to form the common bile duct. The common bile duct then empties into the duodenum . Composition:- Bile primarily consists of water, bile salts, bile pigments, electrolytes, & to a lesser extent, cholesterol and fatty acids. The hepatic cells lining the bile canaliculi are responsible for the production of bile. The production of bile appears to be an active secretion process

Biliary excretion of drugs A drug to be excreted by bile must have following properties: Molecular weight : Mol wt > 500 Da excreted via bile Mol wt < 300 excreted via kidney Mol wt b/w 500 & 300 via both Must be highly polar such as metabolic conjugates. Glucuronidation etc (Formation of glucuronide conjugates increases mol. Wt by 200 ) Examples of drugs excreted via bile are: Digitalis glycosides, Bile salts, Cholesterol, Steroids, indomethacin The efficacy of drug excretion by the biliary system can be tested by an agent that is exclusively and completely eliminated unchanged in the bile, e.g. sulfo-bromo-phthalein .

Biliary excretion of drugs Compounds that enhance bile production stimulate the biliary excretion of drugs normally eliminated by this route. Eg, phenobarbital , which induces many mixed-function oxidase activities, may stimulate the biliary excretion of drugs by two mechanisms: by an increase in the formation of the glucuronide metabolite and by an increase in bile flow . In contrast, compounds that decrease bile flow or pathophysiologic conditions that cause cholestasis, decrease biliary drug excretion. The route of administration may also influence the amount of the drug excreted into bile. For example, drugs given orally may be extracted by the liver into the bile to a greater extent than the same drugs given intravenously.

Estimation of biliary clearance

enterohepatic circulation A drug or its metabolite is secreted into bile and upon contraction of the gallbladder is excreted into the duodenum via the common bile duct. From intestine the drug or its metabolite will be excreted into the feces or reabsorbed into the systemic circulation. The cycle in which drug is absorbed, secreted into the bile and reabsorbed from the intestine is called enterohepatic circulation . Some drugs excreted as a glucuronide conjugate become hydrolyzed in the gut back to the parent drug by the action of a b - glucuronidase enzyme present in the intestinal bacteria. In this case, the parent drug becomes available for reabsorption. Eg, morphine, chloramphenicol, cromoglycate .

Double peak phenomena Some drugs like cimetidine and ranitidine, after oral administration produce blood concentration curve consisting of two peaks. The presence of double peaks has been attributed to variability in stomach emptying , variable intestinal motility , presence of food , enterohepatic cycle or failure of a tablet dosage form .

Significance of Biliary Excretion When a drug appears in the feces after oral administration, it is difficult to determine whether this presence of drug is due to biliary excretion or incomplete absorption. If the drug is given parenterally and then observed in the feces, one can conclude that some of the drug was excreted in the bile. Because drug secretion into bile is an active process, this process can be saturated with high drug concentrations. Moreover, other drugs may compete for the same carrier system . With a large dose or multiple doses, a larger amount of drug is secreted in the bile, from which drug may then be reabsorbed. This reabsorption process may affect the absorption and elimination rate constants . Furthermore, the biliary secretion process may become saturated, thus altering the plasma level–time curve .

Significance of Biliary Excretion Drugs that undergo enterohepatic circulation sometimes show a small secondary peak in the plasma drug–concentration curve. The first peak occurs as the drug in the GI tract is depleted; a small secondary peak then emerges as biliary-excreted drug is reabsorbed. This is known as double peak phenomena . Eg, ranitidine, cimetidine In animals , bile duct cannulation provides a means of estimating the amount of drug excreted through the bile. In humans, a less accurate estimation of biliary excretion may be made from the recovery of drug excreted through the feces . However, if the drug was given orally, some of the fecal drug excretion could represent unabsorbed drug.

Factors affecting biliary drug excretion Molecular Weight of drug Polarity of drug Pathological condition Route of administration

MOL. WT OF DRUGS Drugs having mol. Wt greater than 500 are mainly excreted by bile while drugs having mol. Wt. b/w 300-500 are excreted by both kidney and liver and those having mol. Wt ≤ 300 are excreted through kidney POLARITY OF DRUG Drugs or metabolite having high molecular weight & highly polar groups are excreted more via this pathway As most of drug metabolites are glucuronide conjugates & the formation of glucuronide increases the molecular weight of compound by 200 and above increases its polarity and thus excretion

PATHOLOGICAL CONDITION P athophysiologic conditions that cause cholestasis (condition where bile cannot flow and reach the duodenum) decrease biliary drug excretion. e.g . half life of drug is about twice as long in patients with biliary obstruction than patients having no obstruction ROUTE OF ADMINISTRATION May also influence the amount of drug excreted into the bile e.g. drugs given orally may be extracted by the liver into the bile to a greater extent than if the drugs are given intravenously

ROLE OF TRANSPORTERS ON HEPATIC CLEARANCE AND BIOAVAILABILITY Class 1 drugs are not so much affected by transporters because absorption is generally good already due to high solubility and permeability. Class 2 drugs are very much affected by efflux transporters because of low solubility and high permeability . The limited amount of drug solubilized and absorbed could efflux back into the GI lumen, thus resulting in low plasma level. Further, efflux transporter may pump drug into bile if located in the liver canaliculi .

Elimination of drug through other organs

Elimination of drug through other organs Pulmonary excretion Salivary excretion Mammary excretion Skin excretion Genital excretion

1. Pulmonary excretion Organ involved= Lungs Lungs contains various drug metabolizing enzymes Appropriate route for gaseous and volatile substances due to its anatomical position in circulatory system, large alveolar area and high blood flow . E.g. alcohol, and many gaseous anesthetics The breathalyzer test based on quantitative pulmonary excretion of ethanol.

2. Salivary excretion Saliva volume is 1-2 liters per day with flow rates ranging from 0.5 ml/min. Saliva pH ranges from 6.2 - 7.4. It also contains a number of enzymes including amylase, ptylin , lipase and esterases . The excretion of drugs in saliva is determined largely by pH-partition properties Examples of drugs excreted in saliva are: sulfonamides, phenobarbital, rifampicin, phenytoin, theophylline, salicylates, acetaminophen, digoxin etc. In many cases salivary concentration represents the free drug concentration in plasma. Can act as a mean of monitoring plasma concentration if the partition coefficients between plasma and saliva remain constant e.g. rifampicin The bitter after taste in the mouth of a patient on medication is an indication of drug excretion in saliva. May also result in localized side effects e.g. black hairy tongue (antibiotics), gingival hyperplasia (phenytoin)

2. Salivary excretion Transport of drugs from blood to saliva depends on Lipid solubility of drug pH of saliva pKa of drug Plasma protein binding Secretion of drugs in saliva is usually passive process but active transport may be involved . Drugs which are excreted in saliva can undergo recycling similar to biliary cycling e.g. sulfonamides and clonidine - Salivary recycling

3. Mammary excretion Excretion of drugs in milk is a passive process and is dependent upon pH partition behavior, molecular weight, lipid solubility and degree of ionization. pH of milk ranges from 6.4 - 7.6 Free , unionized, lipid soluble drugs diffuse into the mammary cells passively. The extent of drug excretion in milk can be determined from milk/plasma drug concentration ratio ( M/P ). Since milk is acidic comparison to plasma, as in the case of saliva, weakly basic drugs concentrate more in milk and have M/P ratio greater than 1. The opposite is true for weakly acidic drugs.

3. Mammary excretion The amount of drug excreted in milk is generally less than 1 % . The infant’s immature renal and hepatic function can delay excretion or metabolic inactivation of drugs. This could lead to accumulation in infant’s blood. S ome potent drugs such as barbiturates and morphine may induce toxicity in infants. Discoloration of teeth with tetracycline and jaundice due to interaction of bilirubin with sulfonamides are examples of adverse effects precipitated due to drug excretion in the milk. Nicotine is also secreted in the milk of mothers who smoke. Thus , wherever possible, nursing mothers should avoid drugs and smoking and if medication is unavoidable, the infant should be bottle fed.

4. Skin excretion Some drugs are excreted through skin but it is of little importance Arsenic and mercury are excreted in small quantities through the skin in sweat. Sweat is found at moderately acidic to neutral pH levels, typically between 4.5 and 7.0 . Drugs excreted through the skin via sweat also follow pH-partition hypothesis . Passive excretion of drugs and their metabolites through skin is responsible to some extent for the urticaria and dermatitis and other hypersensitivity reactions. Compounds such as benzoic acid, salicylic acid, alcohol and heavy metals like lead, mercury and arsenic are excreted in sweat . Disadvantage of this route include difficulty in collecting sweat samples.

5. Genital excretion Reproductive tract and genital secretions may contain the excreted drugs. Some drugs have been detected in semen eg. antiretroviral drugs like lamivudine

EXCRETION PATHWAYS, TRANSPORT MECHANISMS & DRUG EXCRETED Excretory route Mechanism Drug Excreted Urine GF/ ATS/ ATR, PTR Free, hydrophilic, unchanged drugs/ metabolites of MW< 300 Bile Active secretion Hydrophilic, unchanged drugs/ metabolites/ conjugates of MW >500 Lung Passive diffusion Gaseous &volatile, blood & tissue insoluble drugs saliva Passive diffusion Active transport Free, unionized, lipophilic drugs. Some polar drugs Milk Passive diffusion Free, unionized, lipophilic drugs (basic) Sweat / Passive diffusion Free, unionized lipophilic drugs

References: - Applied Pharmacokinetics by LEON SHARGEL, 7 th edition, pg 309-350 -BIOPHARMACEUTICS by Milo Gibaldi - Kulkarni -Biopharmaceutics by G ul majid khan

Drugs that are competitive inhibitors of each other for drug protein binding may affect clearance of each other. Drugs which influence the hepatocytes function , effect the extraction ratio and hence the hepatic clearance. Similarly, in case of hepatic diseases , the blood flow to the liver and its metabolizing activity is altered, which ultimately influence the hepatic clearance .

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Clearance & Elimination detail explanation.pptx