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Vol. 29, Issue 10, 1332-1336, October 2001

Influence of Microsomal Concentration on Apparent Intrinsic Clearance: Implications for Scaling in Vitro Data

J. Cory Kalvass, David A. Tess, Craig Giragossian, Michael C. Linhares, and Tristan S. Maurer

Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development Groton, Connecticut

The influence of microsomal concentration on unbound fraction (fumic), half-life (t1/2), apparent intrinsic clearance (CLint,app) and apparent Michaelis-Menten constant (Km,app) was examined for two compounds, one representative of high nonspecific binding to microsomes (compound A) and one representative of low (compound B). Kinetic parameters were estimated for the two probe compounds at two human microsomal protein concentrations (0.46 and 2.3 mg/ml) and cytochrome P450 concentrations (0.20 and 1.0 µM), representing a 5-fold difference in microsomal concentration. For compound A, fumic and CLint,app were inversely proportional to microsomal concentration. Conversely, the Km,app of compound A was proportional to microsomal concentration and the half-life was unchanged. For compound B, half-life was inversely proportional to microsomal concentration. In this case, fumic, CLint,app, and Km,app were not proportionally influenced. The experimental observations were entirely consistent with that predicted by a mathematical relationship between microsomal concentration, fumic, t1/2, CLint,app, and Km,app. These results demonstrate that when nonspecific binding is extensive, CLint,app is dependent on the arbitrary choice of microsomal concentration included in the incubation.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 2001 by the American Society for Pharmacology and Experimental Therapeutics.