Pharmacokinetics absorption,distribution,metabolism,excretion

ADME

1. PHARMACOKINETICS- ABSORPTION HEENA PARVEEN, ASST.PROFESSOR, PHARMACOLOGY DEPT.

2. PHARMACOKINETICS- ABSORPTION Absorption is the process by which drugs enter the systemic circulation. Absorption of a drug from various sites, its movement among various body compartments and its distribution within the cell are all determined by the properties of the drug and those of biological membranes in the body .

3. For understanding the drug absorption, drugs can be divided into three groups : (1) Those that do not ionise , are non-polar and lipid soluble and hence, are easily diffusible . (2) Those that always get ionised , are water soluble polar (lipid insoluble); and almost nondiffusible ; and (3) Those that are partly ionised and partly non- ionised and hence partly water soluble and partly lipid soluble. Weakly acidic drugs remain unionised at acidic pH; whereas weakly basic drugs remain unionised at alkaline pH.

4. Information regarding the rate of absorption of a drug is necessary : To determine the frequency of its administration. To ascertain the duration of effective action; and To predict the onset of desired or undesired effects of the drug. The time between the administration of a drug and the development of response is known as the biological lag. The route of administration determines the biological lag . Oral absorption mostly occurs in the upper GI tract. Drugs given orally may be inactive systemically because of: Enzymatic degradation of polypeptides within the lumen of the GI tract e.g. insulin, adrenocorticotropic hormone (ACTH ). Poor absorption from the GI tract e.g. aminoglycoside antibiotics; or Inactivation by first pass metabolism.

5. Bioavailability of a drug is defined as the amount or percentage of an active drug that is absorbed from a given dosage form following its non-vascular administration, and reaches systemic circulation, to be available at the desired site of action. When the drug is given IV, the bioavailability is 100 %. Single dose bioavailability test involves an analysis of plasma or serum concentration of the drug at various time intervals after its oral administration and plotting a serum concentration time curve. The area under such a curve (AUC) provides information about the extent (amount of drug absorbed) and the rate of absorption as well as the time required ( Tmax ) to achieve the maximum concentration ( Cmax ). The bioavailability ‘F’ is determined by comparing the AUC after oral administration of a drug with the AUC after IV administration of the same dose of the drug.

6. The plasma drug level curves following oral administration of three formulations of the same basic drug. MTC = minimum toxic concentration, MEC = minimum effective concentration . The peak area indicates the therapeutic range. For formulation A and B, the areas under the curves are identical . However, formulation A would produce quick onset and short duration of action compared to formulation B whose effect would last much longer. Formulation C gives inadequate plasma levels and is , therefore, likely to be therapeutically ineffective.

7. Bioavailabilty is reduced if absorption is reduced or if the drug is metabolized before getting into the circulation . Factors affecting drug absorption and its bioavailability are : I Physical properties: Physical state: Liquids are absorbed better than solids and crystalloids are absorbed better than colloids. Lipid or water solubility: Drugs in aqueous solution mix more readily than those in oily solution with the aqueous phase at the absorption site, and hence are absorbed faster. However, at the cell surface, the lipid soluble drugs penetrate into the cell more rapidly than the water soluble drugs . Bile salts emulsify the fat soluble vitamins A and D in the small intestine and assist their absorption.

8. II Dosage forms: Particle size : The particle size of sparingly soluble drugs can affect their absorption. A tablet that contains large aggregates of the drug may not disintegrate even on prolonged contact with gastric and intestinal juices and hence, may be poorly absorbed. Small particle size is important for absorption of corticosteroids, antibiotics like chloramphenicol and griseofulvin , certain oral anticoagulants and spironolactone . By reducing the particle size, the dosage of the active drug can be reduced without lowering its efficacy. On the other hand, for an antihelminthic such as bephenium hydroxynaphthoate , the particle size should be large enough to reduce its absorption. Particle size is of no consequence in the case of freely water soluble drugs .

9. Disintegration time and dissolution rate: The effect of the physical factors is commonly evaluated by determining : ( i ) The disintegration time which measures the rate of break up of the tablet or the capsule into the drug granules ; and (ii) The dissolution rate which is the rate at which the drug goes into solution. The disintegration time of a tablet is a poor measure of the bioavailability of the contained drug. This is because, in addition to disintegration time and particle size, other factors such as crystalline form (polymorphism), saturation solubility and solvation can modify the bioavailability of a drug. The dissolution rate is perhaps a better parameter . Formulation: The method of formulation can markedly influence the drug absorption and thus determine its bioavailability. Usually, substances like lactose, sucrose, starch and calcium phosphate or lactate are used as inert diluents in formulating powders or tablets. Such fillers may not be totally inert but may affect the absorption as well as stability of the medicament. Thus, calcium and magnesium ions reduce the absorption of tetracyclines , while calcium phosphate used as a diluent for calciferol has caused calcium toxicity, when given in large doses. Replacement of calcium phosphate by lactose made a marked difference in the efficacy of a reformulated phenytoin preparation. A faulty formulation can render a useful drug therapeutically useless. The study of the influence of formulation on the therapeutic activity of drugs is known as biopharmaceutics .

10. III Physiological factors : Ionisation : The mucosal lining of the GI tract is impermeable to ionised form of weak organic acids and weak organic bases . At the body pH, most drugs exist in two forms : (1) an unionised component, predominantly lipid soluble; and ( 2) an ionised , water soluble component. The unionised fraction can cross the cell membrane rapidly. The amount of the drug which crosses the gut wall is determined by the gradient of its concentration between the lumen of the gut and the portal venous blood. If the plasma concentration of a drug present in a free, unionised form, is rapidly reduced by binding with plasma proteins, its absorption from the gut lumen is enhanced . pH of the GI fluid and the blood: Weakly acidic drugs are rapidly absorbed from the stomach as they exist in the acidic medium of the stomach in an unionised form. They act rapidly on oral administration e.g., salicylates and barbiturates . However, most of the weakly acidic drugs are also absorbed from the duodenum because of their solubility in the alkaline medium and the large absorbing surface area.

11. The effect of food on drug absorption: Increased peristaltic activity, as in diarrhoea , reduces the drug absorption. Anticholinergic drugs, which prolong gastric emptying time, also impair absorption of drugs . Enterohepatic cycling: involves drug excretion into the intestine after its absorption, followed by its reabsorption . This increases the bioavailability of a drug, e.g., morphine . Area of the absorbing surface and local circulation: Drugs are absorbed better from the small intestine than from the stomach because of the larger surface area of the former. Reduction in the absorbing surface following major GI resection, reduces the drug absorption. Increased vascularity can increase absorption . First pass elimination: The bioavailability of certain drugs is reduced by rapid metabolic degradation during the first passage through the gut wall ( isoprenaline ) or the liver ( propranolol ). The other examples are opioids , beta-adrenergic blockers, progesterone, isosorbide dinitrate etc .

12. Presence of other agents : Vitamin C enhances the absorption of oral iron, while phytates retard it. The absorption of fat-soluble vitamins is reduced in the presence of liquid paraffin, whereas cholesterol absorption is reduced by sitosterol . Calcium, present in milk and in antacids, forms insoluble complexes with the tetracyclines and reduces absorption. Disease states : Structural changes in the GI mucous membrane result in mal absorption syndrome. Gastrointestinal mucosal edema significantly depresses the absorption of drugs such as hydrochlorothiazide in patients with congestive heart failure. Absorption and first pass metabolism may be affected in c onditions like thyrotoxicosis , achlorhydria , cirrhosis of the liver and biliary obstruction.

13. PHARMACOKINETICS- DISTRIBUTION After absorption, a drug enters or passes through the several body fluid compartments depending upon its physicochemical properties

14. The apparent volume of distribution ( Vd ) is defined as the volume into which the total amount of a drug in the body appears to be uniformly distributed . It is calculated as the total amount of drug in the body divided by the concentration of the drug in the plasma at zero time. For many drugs, ( Vd ) is constant over a wide dosage range. Vd (L) = Total amount administered Plasma concentration Some drugs pass into the cells whereas others are distributed extracellularly . However, a drug can penetrate into and exist in more than one compartment.

15. The rate of passage of a drug through a membrane is dependent upon the pH of the body compartment and the dissociation constant ( pK ) of the drug . pK is the pH at which the nonionised and ionised drug concentrations are equal. Nonionised , lipid soluble drugs (the vast majority) readily cross membranes and are distributed throughout the body; they have large volumes of distribution. Drugs which are highly protein bound (e.g. warfarin ) or ionized ( gentamicin ) remain largely within the vascular compartment and have very low volumes of distribution.

16. Plasma concentration of a drug: This depends upon the drug’s Rate of absorption Distribution Metabolism; and Excretion After absorption, the drug circulates in the blood either in the free form or bound to plasma proteins-either albumin or alpha-acid-glycoprotein. These proteins are termed as acceptors. Albumin is the main binding protein for many endogenous substances and drugs. The fraction bound to protein usually falls as the total concentration of the drug increases and the binding sites get saturated.

17. Binding of drugs to plasma proteins assists absorption Protein binding: Acts as a temporary ‘store’ of a drug and tends to prevent large fluctuations in concentration of unbound drug in the body fluids . Reduces diffusion of the drug into the cells and thereby delays its metabolicdegradation e.g. 90 % of long-acting sulfonamides and 98% of warfarin circulate in bound form whereas protein binding is negligible with ethosuximide and amoxycillin . Reduces the amount of drug available for filtration at the glomeruli and hence delays its excretion. Reduces the drug clearance . Reduces concentrations of free drug to be available for desirable effect e.g. highly protein bound sulfonamides like sulfadoxine may have too low concentration in interstitial fluid, CSF and tissue cells to combat dangerous infections.

18. Drug storage: The concentration of a drug in certain tissues such as fat and liver after a single dose may persist even when its plasma concentration has decreased to low or undetectable levels . Many lipid soluble drugs are stored in the body fat depots e.g. on IV administration, 70 % thiopentone is taken up by the body fat from which it is released slowly. Because of such storage , repeated exposure to certain chemicals (e.g. DDT), even in small doses, may lead to chronic toxicity . Placental transfer: There are a number of influx transporters in placenta making the placental barrier imperfect. The effect on the fetus is determined by its gestational age. Blood Brain Barrier: Ionisable organic molecules (which many drugs are) are largely denied such passage from blood into the brain. However, substances can pass freely between CSF in the subarachnoid space and the ECF in the brain; hence, drugs such as antibiotics introduced into the CSF can enter the brain ECF in adequate concentration. Drugs may penetrate into the brain using uptake transporters for endogenous substances and nutrients.

19. PHARMACOKINETICS- METABOLISM

20. The changes that a drug (foreign substance to body- xenobiotic ) undergoes in the body and its ultimate elimination are considered as the fate of the drug. Alteration of a drug within a living organism is known as bio-transformation . After absorption, drugs could undergo three possible fates: Metabolic transformation by enzymes: which may be microsomal , cytosolic or mitochondrial . The metabolism of drugs usually : (1) Inactivates an active drug; or (2) Activate an inactive drug ( prodrug ); or (3) Generate active metabolite(s) of an active drug.

21. Spontaneous change into other substances without the intervention of enzymes Meclhorethamine E thyleniminium cations Inactive Alkaline pH of plasma Active Excreted unchanged: If a drug is already highly polar and water soluble, it is not metabolised and gets excreted as such, e.g. aminoglycosides . Hepatic microsomal enzymes: These enzymes are located in the liver microsomes which form a part of the smooth membrane of the endoplasmic reticulum of the hepatic cells. Among these enzymes are those which catalyse a variety of oxidative and reductive reactions. e.g., superfamilies of enzymes- cytochrome P 450 (CYP ), flavin containing monooxygenases (FMO) and epoxide hydroxylases (EH) , phase II enzymes like esterases , amidases , glucuronyl transferases .

22. Microsomal enzyme systems are accessible only to substances with a high oil/water partition coefficient. These enzymes alter drugs to make them more polar and water soluble, so that they can be excreted by the kidneys. CYPs are involved in the metabolism of many dietary and xenobiotic compounds and in synthesis of endogenous agents . ( e.g. steroids, bile acids from cholesterol). CYP450 is so named because it absorbs light maximally at 450 nm . A drug bound to cytochrome P450 may be either oxidised or reduced . There are many isozymes of the enzyme CYP450, each of which is encoded by a separate gene; 50 are functionally active. Variations in their gene structure explain the differences in the drug metabolism among different individuals and ethnic groups.

23. The naming of the isozymes follows an orderly pattern. e.g. in the name CYP3A4, 3 stands for the family, A for the subfamily, and 4 for the chromosome encoding gene . CYP3A4 is involved in the metabolism of several drugs, followed by CYP2D6. The other important isoenzymes are CYP2C9, CYP2C19 and CYP1A2. FMOs are minor contributors to drug metabolism. H2 receptor antagonists, clozapine , itopride are metabolised by them. The metabolites are benign and cause no drug-drug interaction .

24. EH deactivates potentially toxic metabolites produced byCYPs . e.g . carbamazepine 10,11 epoxide , an active metabolite of the carbamazepine is inactivated by microsomal EH. Non- microsomal enzymes: Drugs are also metabolised by non- microsomal enzymes, present in liver, plasma and tissues including placenta and even by those present in the intestinal micro-organisms ( microfloral enzymes) . e.g . MAO, alcohol dehydrogenase , xanthine oxidase .

25. The xenobiotic enzyme reactions involved in metabolic transformations are : Phase I (Non-synthetic): Oxidation Reduction Hydrolysis; and Phase II (Synthetic): Synthesis (conjugation or transfer reactions).

26. Phase I (Non-synthetic): The Metabolism of drugs is essentially a detoxification process. Oxidation, reduction and hydrolysis introduce polar groups such as Hydroxyl , amino, Sulfhydryl and Carboxy into drugs which are consequently made water soluble and pharmacologically less active. D uring the initial stages of metabolism of certain drugs, active and even toxic compounds may be produced. Ex: Parathion Paraxone Inactive insecticide Active toxic compound

27. Oxidation: A drug may be oxidised by more than one mechanism and for the same drug this may differ in different species of animals. The reactions include : Microsomal oxidation which involves: ( i ) Hydroxylation, wherein hydroxyl group is introduced into the drug molecule. Ex: conversion of salicylic acid to gentisic acid.

28. (ii) Dealkylation , wherein an alkyl group is removed . e.g . conversion of phenacetin to the active compound p- acetaminophenol .

29. (iii) Deamination , wherein an amino group is removed e.g. conversion of amphetamine to benzyl-methyl- ketone . Non- microsomal oxidation : e.g. ethyl alcohol is oxidised to carbon dioxide and water . Methyl alcohol is oxidised to toxic formic acid and formaldehyde .

30. Mitochondrial oxidation : A mitochondrial enzyme monoamine oxidase (MAO) causes oxidative deamination of substances like adrenaline, 5-HT and tyramine . Reduction: Many halogenated compounds and nitrated aromatic compounds are reduced by the microsomal enzymes . e.g . halothane and chloramphenicol ; drugs like chloral hydrate, disulfiram and nitrites are reduced by non- microsomal enzymes . Hydrolysis: This is usually carried out by enzymes ‘ carboxy esterases ’ that hydrolyse (split with addition of water) the esters and amide containing compounds . These enzymes are microsomal , non- microsomal and microfloral in origin.

31. Drugs like pethidine , procaine,acetylcholine , diacetylmorphine, atropine, neostigmine and phenytoin , are hydrolysed by esterases . Digitalis glycosides are rendered inactive by hydrolysis . Phase II reactions: Conjugation or transfer reaction: This is a synthetic process by which a drug or its metabolite is combined with an endogenous substance, resulting in various conjugates such as glucuronides , ethereal sulphates , methylated compounds and amino acid conjugates .

32. Glucuronides are produced by the combination of a hydroxyl, carboxyl or amino group of drug molecule with glucuronic acid . Compounds like morphine,PABA , stilboesterol , salicylic acid and phenol are excreted mainly in the form of glucuronides . A classical example of amino acid conjugation is the combination of benzoic acid with glycine to form hippuric acid.

33. PHARMACOKINETICS- EXCRETION

34. The important channels of Drug Excretion are : Kidneys : The processes which determine the elimination of a drug in the urine are Passive glomerular filtration: Only the unbound fraction of unionized drugs is filtered at the glomerulus ; but they are reabsorbed by diffusion back from the tubular lumen into the cells lining the tubules. Thus, ultimately a very small amount of the drug appears in the urine. Ionised drugs which are poorly absorbed are excreted almost entirely by glomerular filtration and are not reabsorbed . Active tubular secretion: Many weak acids (anionic substances) and weak bases ( cationic substances ) are actively secreted by proximal tubules by carrier-mediated systems involving transporters such as p-glycoprotein and the multidrug-resistance-associated protein type 2 (MRP2). These transporters are also responsible for excretion of conjugated metabolites of drugs

35. Passive renal tubular reabsorption : Passive diffusion is a bidirectional process and drugs may diffuse across the tubules in either direction depending upon the drug concentration , lipid solubility and the pH e.g. salicylates . Lungs: Volatile general anaesthetics and drugs like paraldehyde and alcohol are partially excreted by the lungs. Their presence can be recognised by the odour they impart to the breath. Bile: Transport systems similar to those in the kidneys are present in the hepatocytes which actively secrete drugs and their metabolites into the bile. Drugs such as phenolphthalein , doxycycline and cefoperazone appear in high concentrations in the bile. Such drugs may get repeatedly reabsorbed from the intestine and re-excreted in bile, thereby exerting a prolonged action.

36. Intestines: Drugs and their metabolites can be actively secreted from the systemic circulation into the intestinal lumen using transporters such as p-glycoprotein present in the enterocytes . Further, drugs can passively diffuse from the blood into the intestinal lumen , depending on their pK and the luminal pH . Laxatives like cascara and senna , which act on the large bowel are partly excreted into that area from the blood stream, after their absorption from the small intestine . Heavy metals are also excreted through the intestine and can produce intestinal ulceration.

37. Skin: Arsenic and heavy metals like mercury are excreted in small quantities through the skin . Arsenic gets incorporated in the hair follicles on prolonged administration. This phenomenon is used for detection of arsenic poisoning. Saliva and milk: Certain drugs like iodides and metallic salts are excreted in the saliva. Lead compounds deposited as lead sulfide produce a blue line on the gums. Excessive salivation is a frequent symptom of chronic, heavy metal poisoning.

38. THA9K UH!