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)
F×D
CLT =
AUC
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
rate of elimination from the body
CLT =
Cp
Total Clearance (CLT)
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
Clearance
CL 
rate of eliminatio
n
Cp
total clearance:
CL T 
rate of eliminatio
n from the body
Cp
organ clearance:
CL 
rate of eliminatio
n from an organ
Cp
hepatic clearance: CL H 
rate of eliminatio
renal clearance:
rate of eliminatio
CL R 
n from liver
Cp
Cp
n from kidney
Plasma vs. Blood Clearance
Rate of elimination = CLp X Cp
Rate of elimination = CLb X Cb
CLp X Cp = CLb X Cb
CL p
CL b

Cb
Cp
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,
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
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?
Hepatic Clearance
CLH = CLM, H + CLbiliary
CLM,H :
hepatic metabolic clearance
CLbiliary :
biliary excretory clearance
Hepatic Clearance
returning to the
circulation
Blood flow, Extration Ratio and Blood Clearance
(elimination)
returning to the
circulation
CL b 
Rate of eliminatio
CA
Blood
n
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
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
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
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)
EH of Example Drugs
Effect of fu & Q on CLH
CL
H
Q
H
E
H
Q
H
f u CL
(
Q
 when EH > 0.7 (fuCLint > 2.3 QH),
H
int
 f u CL
)
int
CLH ~ QH
nonrestrictive clearance insensitive to changes in fu
sensitive to changes in QH
 when EH < 0.3 (QH > 2.3 fuCLint),
restrictive clearance
CLH ~ (fu)(CLint)
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
i.e. when complete absorbed into the intestinal
epithelium and no GI metabolism
fu CL int
QH
F =1- EH =1=
Q H + fu CL int Q H + fu CL int
 when EH > 0.7 (fuCLint > 2.3 QH),
F 
Q
H
f u CL
int
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
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
CL R 
rate of eliminatio
n from kidney
C
For an intravenous drug,
in urine
IV
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
Renal Clearance
rate of renal excretion = rate of glomerular filtration +
(rate of tubular secretion – rate of tubular reabsorption)
renal
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
 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
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.