Renal clearance

methods for determining renal clearance, factors affecting renal clearance

1. WELCOME 1

2. Presented By Archana S Nair M Pharm Part 1 Pharmaceutics RENAL CLEARANCE 2

3. contents Introduction. Clearance models. Physiologic or organ clearance. Model independent methods. Renal clearance. Comparison of drug excretion methods. Relationship between renal clearance values & mechanism of clearance. Graphical method & model independent method. Creatinine clearance, total body clearance. Factors affecting renal excretion or renal clearance. References 3

4. INTRODUCTION DRUG CLEARANCE Pharmacokinetic term Hypothetical volume of body fluids containing drug from which drug is removed or cleared completely in a specific period of time. Unit- ml/min or litre/hour Total body clearance is the sum of individual clearances by all eliminating organs. Body clearance= k e V D +k l V D +k m V D = kV D 4

5. INTRODUCTION Cl T is the rate of drug elimination divided by the plasma drug concentration Cl T = elimination rate plasma drug concentration(C p ) Cl T = dDE /dt = mL/min C p D E = amount of drug eliminated dD E /dt = rate of elimination Elimination rate = dD E =C p Cl T dt First order elimination rate , dDE/dt=kC p V D Cl T = kC p V D = kV D C p 5

6. Clearance models Calculation from k and VD assumes a model. Estimated directly from plasma concentration time curve does not assume any model. Compartment model Physiologic model Model independent 6

7. Physiologic /organ clearance Clearance may be calculated for any organ involved in the irreversible removal of drug from the body. Kidneys and liver. Physiologic models are based on drug clearance through individual organs or tissue groups. Fraction of blood volume containing drug that flows through the organ and is eliminated of drug per unit time. Clearance = blood flow (Q) × extraction ratio (ER) ER = Ca-Cv Ca Cl = Q(Ca – Cv) Ca 7

8. Physiologic /organ clearance Blood flow rate and the ability of organ to eliminate the drug. Require invasive techniques to obtain measurements of blood flow and extraction ratio. Q Ca Q Cv elimination drug Elimination organ Q= blood flow Ca= incoming drug concentration Cv= outgoing drug concentration 8

9. Model independent methods Plasma drug concentration time curve. Calculate certain pharmacokinetic parameters - clearance and bioavailability. Advantage s – No assumption for a specific compartment model is required to analyze the data. The volume of distribution and the elimination rate constant need not be determined . 9

10. Model independent methods Clearance may be determined directly from the plasma – time concentration curve by D0= dose C(t)= unknown function that describes the declining plasma drug concentration. 10

11. Model independent methods Compartment model static volume and first-order elimination is assumed plasma flow is not considered. ClT = k V D Physiologic model Qca Q Cv ClT=Q ER Model independent ? k V D Cp ?V Cp Elimination 11

12. Renal clearance Volume of plasma that is cleared of drug per unit of time through the kidney. Constant fraction of V D in which the drug is contained that is excreted by the kidney per unit of time. 12

13. Renal clearance Consider the mass balance of drug cleared by the kidney and ultimately excreted in urine. Rate of drug passing through kidney = rate of drug excreted in urine = renal clearance = plasma drug concentration = rate of urine flow = urine drug concentration excretion rate = Cp 13

14. Comparison of drug excretion methods Cl R = Rate of (filtration + secretion – reabsorption) Plasma drug concentration. Renal clearance ratio = Cl R of drug Cl R of creatinine. Actual clearance is not obtained by direct measurement. Compared to that of standard reference standard such as inulin. Clearance ratio indication for the mechanism of renal excretion of the drug. 14

15. RELATIONSHIP BETWEEN RENAL CLEARANCE VALUES & MECHANISM OF CLEARANCE Renal clearance(ml/min ) Renal clearance ratio Mechanism of renal clearance Examples (least value) Drugs filtered and reabsorbed Glucose <130 Above 0 Below 1 Drugs filtered and reabsorbed partially Lipophilic drugs 130(GFR) 1 Drug is filtered only Creatinine, insulin >130 >1 Drug filtered as well as secreted actively Polar, ionic drugs 650(highest value) 5 Clearance equal to renal plasma flow rate Iodopyracet , PAH 15

16. 16 DETERMINATIONOF RENAL CLEARANCE GRAPHICAL METHODS MODEL INDEPENDENT METHODS

17. Graphical methods Slope of the curve obtained by plotting 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, and clearance is greater. For a drug that is excreted slowly through the kidney , the slope is smaller. Clr = Urinary drug excretion rate = dDu/dt Plasma drug concentration Cp 17

18. Graphical methods Rate of drug slope = renal clearance excretion Plasma level( Cp) A B 18

19. Graphical methods Multiplying both sides by Cp gives By rearranging and integrating 19

20. Graphical methods Drug excreted Slope= Cl R in urine(Du) Slope= Cl R 20

21. Model independent methods Nongraphical calculation from the knowledge of , FD , If total amount of drug excreted in urine ( ) has been obtained, then clearance is calculated by 21

22. Model independent methods 22

23. Creatinine clearance Volume of blood plasma that is cleared of creatinine per unit time and is a useful measure for approximating GFR . Used to determine renal function. Endogenous amine produced as a result of muscle catabolism. Excreted unchanged in the urine by glomerular filtration only. Advantage – It can be correlated to steady-state concentration of creatinine in plasma and needs no collection of urine. 23

24. Creatinine clearance Determination of serum creatinine level. Direct method for determining creatinine clearance Normal value – 120 - 130 ml/min. Males 24

25. Total body clearance The sum of individual clearances by all eliminating organs Cl T = k V D Cl R = k e V D Cl H = k m V D Cl T = Cl R + Cl H k= k e +k m 25

26. Factors affecting renal excretion or renal clearance 1. Physicochemical properties of drug 2. Plasma concentration of drug 3. Distribution and binding characteristics of drug 4. Urine pH 5. Blood flow to the kidney 6. Biological factors 7. Drug interactions 8. Disease state 26

27. Factors affecting renal excretion or renal clearance Physicochemical properties of drug Molecular size Drugs with Mol.wt <300, water soluble are excreted in kidney. Mol.wt 300 to 500 Dalton are excreted both through urine and bile. Drugs or metabolites > 500 Daltons, mainly in bile, excreted in urine to a lesser extent. pKa excretion of unchanged drug is inversely related to its lipophilicity. Stereochemical nature of drug 27

28. Plasma concentration of the drug 28

29. Distribution and binding characteristics of the drug Drug with larger V d poorly excreted in urine. Drugs bound to plasma protein cannot be filtered through the glomerulus. Cl R = Urine drug concentration × Urine flow rate Plasma drug concentration F u = C u / C Cl R = F u × Urine flow rate 29

30. Blood flow to kidneys & biological factors BLOOD FLOW TO THE KIDNEYS Increased perfusion increases contact of drug with the secretory sites and enhances their elimination. BIOLOGIC FACTORS Renal excretion is approximately 10% lower in females than in males. Renal function of newborns is 30-40% less in comparison to adults and attains maturity between the age 2.5 to 5 months of age. In old age, GFR is reduced. 30

31. Drug interactions Alteration in P-D binding gentamicin induced nephrotoxicty by furosemide. Alteration of urine pH Acidification of urine with ammonium chloride, methionine or ascorbic acid enhances the excretion of basic drug. Alkalinisation of urine with citrates, tartarates promote excretion of acidic drugs. Competition for active secretion Phenylbutazone competes with hydroxyhexamide for active secretion and thus prolongs its action. Forced diuresis - all diuretics increase elimination. 31

32. Disease state Disease state –renal impairment. Renal dysfunction Impairs the elimination of drugs. Causes of renal failure are hypertension, diabetes mellitus, hypovolemia, nephrotoxic agents like aminoglycosides, phenacetin. Uremia Characterised by impaired glomerular filtration and accumulation of fluids and protein metabolites. Drug accumulation and toxicity may result. 32

33. CONCLUSION The clearance concept was first introduced to describe renal excretion of endogenous compounds in order to measure the kidney function. The term is now applied to all organs involved in drug elimination like liver, lungs, biliary system etc. Clearance values gives useful estimates regarding a lot of disease states. 33

34. references Shargel L, Susanna Wu-pong, Andrew BC. Applied biopharmaceutics and pharmacokinetics :drug elimination and clearance,. 5 th ed. 2009. p.:131-53. Brahmankar DM , Jaiswal BS . Biopharmaceutics and pharmacokinetics: a treatise. 2 nd ed. Delhi: Vallabh prakasan; 2013. p.204-09. www.austincc.edu/emeyerth/clearancehtm.htm www.mhhe.com/biosci/ap/vander/urinary/reang9.mhtm 34

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