Hepatic intrinsic clearance (
CLint) of drugs is often predicted based on
in vitro data that are obtained from the Michaelis–Menten analysis. While most of the metabolic rate-substrate concentration kinetic curves fit to the Michaelis–Menten equation, cytochrome P450 (CYP) and uridine 5′-diphosphate (UDP)-glucuronosyltransferases exhibit sigmoidal kinetics for certain drugs. In our study, the kinetics of CYP3A4-catalyzed carbamazepine 10,11-epoxidation in human liver microsomes was sigmoidal and fitted to the Hill equation, revealing the
S50 value of 358 µ
M,
n of 2.0, and the
Vmax value of 463 pmol/min/mg. While the intrinsic clearance calculated from Michaelis–Menten parameters (
CLint) overestimated the observed
in vivo intrinsic clearance (
CLint, in vivo), the maximum intrinsic clearance calculated based on the Hill equation (
CLmax) exhibited better predictions of
CLint, in vivo. Such better prediction using the
CLmax was also observed for other four drugs, all of which also exhibited sigmoidal metabolic rate-concentration curves, according to the literature data. However, even if we assume such Hill equation, intrinsic clearances predicted at their therapeutic concentrations from
in vitro data were still much lower than their
CLint, in vivo, suggesting the existence of unknown factors causing discrepancy between
in vitro intrinsic clearance in human liver microsomes and
in vivo data. Thus, even if we assume sigmoidal kinetics, that would not be enough for accurate prediction of
CLint, in vivo, and it would be preferable to use
CLmax to quantitatively extrapolate the
in vitro data to
in vivo clearance.
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