clearance concepts quantitative pharmacokinetics dr. chalet tan
TRANSCRIPT
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.