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

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.