clearance concepts quantitative pharmacokinetics dr. chalet tan

Clearance Concepts

Quantitative Pharmacokinetics

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 × V × Cp

Rate of elimination from the body = k × amount in the body

Rate of elimination from the body = CLT × Cp

Definitions:

1. 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.

2. the hypothetical volume of blood/plasma/serum from which the drug is completely removed from the body per unit of time

Total Clearance (CLT)

Clearance

pT

CCL

body thefromn eliminatio of rate

total clearance:

organ clearance: pC

CLorganan fromn eliminatio of rate

pH

CCL

liver fromn eliminatio of rate

pR

CCL

kidney fromn eliminatio of rate

hepatic clearance:

renal clearance:

pCCL

n eliminatio of rate

Plasma vs. Blood Clearance

Rate of elimination = CLb X Cb

Rate of elimination = CLp X Cp

p

b

b

p

C

C

CL

CL

Plasma clearance and blood clearance are equal if Cb: Cp =1

CLp X Cp = CLb X Cb

Additivity of Clearance

For a drug that is eliminated by renal excretion and hepatic metabolism,

Additivity of Clearance

For a drug that is eliminated only by renal excretion and hepatic metabolism,

in urineIV

CLH = (1-fe) CLT

1- fe = the fraction of the IV dose that is eliminated by other mechanisms, usu. hepatic metabolism

Drug A (100 mg) is intravenously injected to a patient. The AUC of plasma drug concentration vs. time curve is 20 g/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?

Hepatic Clearance

CLM,H : hepatic metabolic clearance

CLbiliary : biliary excretory clearance

CLH = CLM, H + CLbiliary

Hepatic Clearance

returning to the circulation

Blood flow, Extration Ratio and Blood Clearance

Ab

C

RateCL

neliminatio of

Blood

(elimination)

returning to the circulation

Blood flow, Extration Ratio and Blood Clearance

EH=0 CA-CV =0, CV=CA

EH=1 CA-CV =CA, CV=0returning to the circulation

0 </= E </= 1

Hepatic (Blood) Clearance

CLb, H= QH X EH

QH: hepatic blood flow

1.35 L/min

EH: hepatic extracton ratio

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

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

Hepatic Extraction Ratio (EH)

CLint: intrinsic hepatic clearance for a drug

Fu,b: free fraction of a drug in blood

Hepatic Extraction Ratio (EH)

EH > 0.7 (fuCLint > 2.3 QH)

EH < 0.3 (QH > 2.3 fuCLint)

drugs are being rapidly eliminated (high CLint)

drugs are being slowly eliminated (low Clint or fu)

CLH ~ QH

EH of Example Drugs

Effect of fu & Q on CLH

)

( int

int

CLfQ

CLfQEQCL

uH

uHHHH

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

Effect of QH on CLH

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?

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?

Effect of EH on F

when EH > 0.7 (fuCLint > 2.3 QH),

F is proportional to QH and inversely proportional to fu

i.e. when complete absorbed into the intestinal epithelium and no GI metabolism

int

CLf

QF

u

H

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?

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?

Renal Clearance

0 ≤ fe ≤ 1

CCLR

kidney fromn eliminatio of rate

For an intravenous drug,

1- fe = the fraction of the IV dose that is eliminated by other mechanisms, usu. hepatic metabolism

in urine

IV

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

Renal Clearancerate of renal excretion = rate of glomerular filtration +

(rate of tubular secretion – rate of tubular reabsorption)

CLR =fuGFR + (CLtubular secretion – CLtubular

reabsorption)

renal

Renal Clearance

CLR = fuGFR when neither secretion nor reabsorption occursFor 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

CLR < fuGFR tubular reabsorption must occur

CLR = fuGFR + (CLtubular secretion – CLtubular

reabsorption)

e. g. para-aminohippuric acid (PHA) is completely secreted from renal plasma and is not reabsorbed, CLR, PHA = renal plasma flow

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

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.

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.