Transl Clin Pharmacol.  2016 Sep;24(3):115-118. 10.12793/tcp.2016.24.3.115.

Revisiting the well-stirred model of hepatic clearance: Q(H), CL(H) and F changing in the same direction

• Yim DS

• KMID: 2351795
• DOI: http://doi.org/10.12793/tcp.2016.24.3.115

Abstract

This tutorial examines the relationship between CL, F, and hepatic blood flow (Q(H)) quantitatively at oral and i.v. administration as an answer to the quiz set for KSCPT members. In case of oral dosing, when hepatic blood flow increases, the hepatic clearance (CL) and bioavailability (F) increases in high-extraction ratio drugs according to the well-stirred model equations for hepatic clearance: CL(H) = Q(H)·ER = Q(H)·f(u)·CL(int)/(Q(H)+f(u)·CL(int)) and F = 1 - ER Despite such a clear relationship, many students may feel it rather paradoxical that the increased CL (thus decreasing the AUC) causes increased F and thus the AUC (F·Dose/CLH) remains unchanged. This tutorial clarifies that the degree to which CL increase fails to match that of the Q(H) increase, and thus the decreased ER (= CL/Q(H)) that results in the increased F. Contemplating this simple, but seemingly paradoxical phenomenon may help students gain a deeper understanding of the first-pass effect.

Keyword

high-extraction ratio; hepatic blood flow; clearance; bioavailability

MeSH Terms

Area Under Curve
Biological Availability
Humans

Figure

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  Figure 1. Analogy of salmon hunting. The high-extraction ratio drug A in our scenario was illustrated as salmon and hepatic enzymes eliminating the drug as brown bears catching the salmon. A fish symbol in the figure roughly represents 10 salmon (= 10 mg of drug A). A) number of survivors: 150 (10 escaped salmon/min x 15 min jumping), B) number of survivors: 210 (21 escaped salmon/min x 10 min jumping).

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  Figure 2. PK profile changes by hepatic blood flow changes in a drug with high-extraction ratio (Drug A in our scenario).

Reference

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2.Rowland M., Tozer TN. Clinical pharmacokinetics and pharmacodynamics: concepts and applications. 4th ed.Lippincott Williams & Wilkins;Baltimore: 2011. 196.

3.Olanoff LS., Walle T., Cowart TD., Walle UK., Oexmann MJ., Conradi EC. Food effects on propranolol systemic and oral clearance: support for a blood flow hypothesis. Clin Pharmacol Ther. 1986. 40:408–414.