Quantitative Pharmacokinetics Clearance Concepts Dr. Chalet Tan

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.

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 If it’s not IV, then you need the F (bioavailability).

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

Clearance total clearance: organ clearance: hepatic clearance: renal clearance:

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

Additivity of Clearance For a drug that is eliminated by renal excretion and hepatic metabolism, When blood is circulating in body, it is circulating in sequence. Entire elimination process is actually additive.

Additivity of Clearance For a drug that is eliminated only by renal excretion and hepatic metabolism, in urine IV Fe is parameter that indicates contribution of renal excretion for final drug elimination. Once we have fe parameter, can use 1 – fe = the fraction of the IV dose that is eliminated by other mechanisms, usu. Hepatic metabolism. CLH = (1-fe) CL 1- fe = the fraction of the IV dose that is eliminated by other mechanisms, usu. hepatic metabolism CLH = (1-fe) CLT

Drug A (100 mg) is intravenously injected to a patient 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? Dose = 100,000 mcg AUC = 20 mcg/(ml)(hr) Then CT = 5 L/hr CLH = CLT - CLR EH = CLH/QH 9

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

Hepatic Clearance returning to the circulation Q x the concentration difference. Elimination is the rate of extraction. Rate of drug being removed/extracted. If we look at total amount of drug as 1, and whatever leaves organ is remaining fraction of 1-E, what survives elimination. 1-E leaves, E is what stays.

Blood flow, Extration Ratio and Blood Clearance returning to the circulation (elimination) Blood Flow or perfusion rate is Q.

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 Value of these equations, especially the last equation, give you a physiological meaning of hepatic clearance. In this case hepatic clearance is actually the product of hepatic blood flow x extraction ratio.

Hepatic (Blood) Clearance CLb, H= QH X EH QH: hepatic blood flow 1.35 L/min EH: hepatic extracton ratio Top relationship gives physiological meaning to the clearance.. But I’m not going to tell you because it’s a secret.

Well-Stirred Model Assume instantaneous and complete mixing of drugs within the liver: Very different hepatic clearnace, due to different intrinsic clearance of the hepatocytes. Hepatic clearance is a function of 3 parameters, hepatic blood flow, hepatic instrinic clearance, and free fraction of the drug in blood. QH: hepatic blood flow CLint: intrinsic hepatic clearance for a drug fu.,b: free fraction of a drug in blood

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) , high extraction ratio drug e. g. propranolol, morphine and verapamil EH < 0.3 (QH > 2.3 fuCLint) , low extraction ratio drug e. g. diazepam, warfarin High extraction ratio drugs get removed rapidly. Low is just not eliminated very rapidly.

Hepatic Extraction Ratio (EH) EH > 0.7 (fuCLint > 2.3 QH) drugs are being rapidly eliminated (high CLint) CLH ~ QH Drug eitehr permeates by diffusion or transported by transporters, to enter hepatocytes, high extraction ratio drugs, the elimination occurs SO rapidly. EH < 0.3 (QH > 2.3 fuCLint) drugs are being slowly eliminated (low Clint or fu)

EH of Example Drugs Few drugs are intermediate.

Effect of fu & Q on CLH when EH > 0.7 (fuCLint > 2.3 QH), CLH ~ QH nonrestrictive clearance insensitive to changes in fu sensitive to changes in QH when EH < 0.3 (QH > 2.3 fuCLint), CLH ~ (fu)(CLint) restrictive clearance proportional to fu insensitive to changes in QH Rate-limited by perfusion, liver can eliminate drug as soon as blood perfuses it into the liver. Not sensitive to changes in protein binding, but very sensitive to changes in hepatic blood flow.

Effect of QH on CLH Lidocaine is high extraction ratio drug. Clearance is directly related to hepatic bloodflow. Antipyrine is VERY low clearance, it’s probably low because of a low extraction ratio. Hepatic blood flow does not increase clearance

In an average 70-kg adult, Drug B has a hepatic blood clearance of 1 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? CLH = 1.2 L/min, fu = 0.05, Q = 1.35 L/min EH = CLH/QH = (1.2 L/min)/(1.35 L/min) = 0.89 Drug B is a high extraction ratio drug. Hepatocytes want to remove this drug. Removal is rate-limited by PERFUSION. The hepatic clearance of drug A is insensitive to changes in plasma protein binding. Fu(prime) = 0.1, CLH(prime) ~ 1.2 L/min b) CLH(prime) = QH(prime) x (EH) = 1.2 L/min x 0.89 = 1.07 L/min 21

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? CLH = 10 mL/min, fu = 0.05, Q = 1.35 L/min EH=CLH/Q = (10 mL/min)/(1.35 L/min) = 0.007 Drug C is a low extraction ratio drug. Clint ~ CLH/fu = 200 mL/min Fu(prime) = 0.1 CLH(prime) ~ fu(prime) x CLINT = 20 mL/min b) CLH(prime) = QH(prime_ x EH = 8.4 mL/min

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 EH is the whole thing. Way to do it is expand the 1 with nominator and denominator when EH > 0.3 (QH > 2.3 fuCLint) F is insensitive to changes in fu or QH

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? ALL OF THE ABOVE HAS BEEN HEPATIC CLEARANCE 24

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? Since low extraction drug, very well absorbed orally, so oral bioavability is not affected by fu/protein binding.

Renal Clearance For an intravenous drug, in urine IV HEPATIC CLEARANCE ABOVE. THIS AND BELOW IS RENAL CLEARANCE. 0 ≤ fe ≤ 1 1- fe = the fraction of the IV dose that is eliminated by other mechanisms, usu. hepatic metabolism

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)?

Renal Clearance GFR = 0.12 L/min GFR is rate that plasma water is being filtered. GFR = 0.12 L/min

Renal Clearance rate of renal excretion = rate of glomerular filtration + (rate of tubular secretion – rate of tubular reabsorption) renal Clearance is rate of elimination divided by [plasma]. Flow rate is GFR x free drug. Free drug because protein bonded drug is too large to filter through glomerular membrane. Rate of filtrations is actually = GFR x fu x [plasma] CLR =fuGFR + (CLtubular secretion – CLtubular reabsorption)

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 CLts and CLtr can only be inferred/observed, can’t be accurately measured. 2 compounds can be used to measure GFR for specific patients. Because more drug is being filtered in than is being cleared by the body. Lipophilic drugs, have VERY inefficient renal clearance, elimination mechanism is mainly by hepatic metabolism. CLR < fuGFR tubular reabsorption must occur e. g. lipophilic drugs are extensively reabsorbed from the renal tubule into the circulation resulting low renal clearance.

Effect of fu on Glomerular Filtration of Drugs As renal clearance increases, protein unbound increases. Renal clearance is = to fu x GFR. Direct proportion. Half-life is a function of 2 independent parameters. A function of volume of distribution and clearance. V = VP + VT x (fu/fuT)

a) What is the renal clearance of Drug G? 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. b) 0.2 x 120 ml/min + 88ml/min = 112 ml/min