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Clearance Concepts

Quantitative Pharmacokinetics. Clearance Concepts. Dr. Chalet Tan. Learning Objectives. total clearance (CL T ) hepatic clearance (CL H ) renal clearance (CL R ). Required reading:

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Clearance Concepts

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  1. Quantitative Pharmacokinetics Clearance Concepts Dr. Chalet Tan

  2. Learning Objectives • total clearance (CLT) • hepatic clearance (CLH) • renal clearance (CLR) Required reading: Tozer & Rowland, Introduction to Pharmacokinetics and Pharmacodynamics, Chapter 5, p70-71, p77-78, p92-99.

  3. Total Clearance (CLT) Rate of elimination from the body = k × amount in the body Rate of elimination from the body = k × V × Cp Rate of elimination from the body = CLT × Cp

  4. Total Clearance (CLT) • Definitions: • a proportionality constant that relates a substance’s rate of elimination from the body at a given time and its blood/plasma/serum concentration at that tine. • the hypothetical volume of blood/plasma/serum from which the drug is completely removed from the body per unit of time

  5. Clearance total clearance: organ clearance: hepatic clearance: renal clearance:

  6. Plasma vs. Blood Clearance Rate of elimination = CLp X Cp Rate of elimination = CLb X Cb CLp X Cp = CLb X Cb Plasma clearance and blood clearance are equal if Cb: Cp =1

  7. Additivity of Clearance For a drug that is eliminated by renal excretion and hepatic metabolism,

  8. Additivity of Clearance For a drug that is eliminated only by renal excretion and hepatic metabolism, in urine IV 1- fe= the fraction of the IV dose that is eliminated by other mechanisms, usu. hepatic metabolism CLH = (1-fe) CLT

  9. Drug A (100 mg) is intravenously injected to a patient. The AUC of plasma drug concentration vs. time curve is 20 mg/ml · h. Drug A is eliminated via hepatic metabolism and renal excretion only, and the fraction of the unchanged drug excreted in urine is 0.3. What is the total body clearance (CLT), hepatic clearance (CLH) and renal clearance (CLR) of drug A?

  10. Hepatic Clearance CLH = CLM, H + CLbiliary CLM,H : hepatic metabolic clearance CLbiliary : biliary excretory clearance

  11. Hepatic Clearance returning to the circulation

  12. (elimination) Blood Blood flow, Extration Ratio and Blood Clearance returning to the circulation

  13. Blood flow, Extration Ratio and Blood Clearance returning to the circulation EH=1 CA-CV =CA, CV=0 EH=0 CA-CV =0, CV=CA 0 </= E </= 1

  14. Hepatic (Blood) Clearance CLb, H= QH X EH QH: hepatic blood flow 1.35 L/min EH: hepatic extracton ratio

  15. Well-Stirred Model Assume instantaneous and complete mixing of drugs within the liver: QH: hepatic blood flow CLint: intrinsic hepatic clearance for a drug fu.,b: free fraction of a drug in blood

  16. Hepatic Extraction Ratio (EH) CLint: intrinsic hepatic clearance for a drug Fu,b: free fraction of a drug in blood • EH> 0.7 (fuCLint > 2.3 QH) , highextraction ratio drug e. g. propranolol, morphine and verapamil • EH< 0.3 (QH > 2.3 fuCLint) , low extraction ratio drug e. g.diazepam, warfarin

  17. Hepatic Extraction Ratio (EH) • EH> 0.7(fuCLint > 2.3 QH) drugs are being rapidly eliminated (high CLint) CLH ~ QH • EH< 0.3(QH > 2.3 fuCLint) drugs are being slowly eliminated (low Clint or fu)

  18. EH of Example Drugs

  19. Effect of fu & Q on CLH • when EH> 0.7(fuCLint > 2.3 QH), CLH ~ QH • nonrestrictive clearance insensitiveto changes in fu • sensitiveto changes in QH • when EH < 0.3(QH > 2.3 fuCLint), CLH ~ (fu)(CLint) • restrictive clearance proportionalto fu • insensitiveto changes in QH

  20. Effect of QH on CLH

  21. In an average 70-kg adult, Drug B has a hepatic blood clearance of 1.2 L/min and is 95% bound to plasma protein. What is the new hepatic blood clearance of drug B, (a) if the plasma protein binding of the drug is decreased to 90%? (b) if the hepatic blood flow is decreased to 1.2 L/min?

  22. In an average 70-kg adult, Drug C has a hepatic blood clearance of 10 ml/min and is 95% bound to the plasma protein. What is the new hepatic blood clearance of drug C (a) if the plasma protein binding of the drug is decreased to 90% ? (b) if the hepatic blood flow is decreased to 1.2 L/min?

  23. Effect of EH on F i.e. when complete absorbed into the intestinal epithelium and no GI metabolism • when EH> 0.7(fuCLint > 2.3 QH), • F is proportional to QH and inversely proportional to fu • when EH> 0.3(QH > 2.3 fuCLint) • F is insensitive to changes in fu or QH

  24. In an average 70- kg adult, Drug D is completely absorbed into the intestinal epithelium following oral administration and does not undergo intestinal metabolism. The oral bioavailability of Drug D is 25%. If the protein binding of the drug is decreased from 99% to 98%, what is the new oral bioavailability?

  25. In an average 70- kg adult, Drug E is completely absorbed into the intestinal epithelium following oral administration and does not undergo intestinal metabolism. The oral bioavailability of Drug E is 75%. If the protein binding of the drug is decreased from 99% to 98%, what is the new oral bioavailability?

  26. in urine IV Renal Clearance For an intravenous drug, 0 ≤ fe ≤ 1 1- fe= the fraction of the IV dose that is eliminated by other mechanisms, usu. hepatic metabolism

  27. Drug F is administered via intravenous infusion to a patient at a rate of 100 mg/h for 10 hours. The steady-state plasma drug concentration is 20 mg/L, a total of 300 mg of the drug is excreted unchanged in the urine. Drug F is only eliminated via renal excretion and hepatic metabolism. What is the total body clearance (CLT), renal clearance (CLR) and hepatic clearance (CLH)?

  28. Renal Clearance GFR = 0.12 L/min

  29. renal Renal Clearance rate of renal excretion = rate of glomerular filtration + (rate of tubular secretion – rate of tubular reabsorption) CLR =fuGFR + (CLtubular secretion – CLtubular reabsorption)

  30. Renal Clearance CLR = fuGFR + (CLtubular secretion– CLtubular reabsorption) • CLR= fuGFR when neither secretion nor reabsorption occurs For substances that are free of plasma protein binding (fu=1), and neither secreted nor reabsorbed, their renal clearance is a measure of GFR (normally 0.12 L/min). e. g. creatinine, inulin • CLR> fuGFR tubular secretion must occur e. g. para-aminohippuric acid (PHA)is completely secreted from renal plasma and is not reabsorbed, CLR, PHA = renal plasma flow • CLR< fuGFR tubular reabsorption must occur e. g. lipophilicdrugs are extensively reabsorbed from the renal tubule into the circulation resulting low renal clearance.

  31. Effect of fu on Glomerular Filtration of Drugs

  32. In an average 70-kg adult, intravenous Drug G is eliminated by renal excretion only. When Drug G is given as i.v. infusion at 1 mg/min, an steady-state plasma concentration of 10 mg/L (fu =0.1) is achieved. a) What is the renal clearance of Drug G? b) If the plasma protein binding of Drug G is decreased to 80%, what is the new renal clearance of Drug G? Assume no saturation in tubular secretion or reabsorption.

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