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Vol. 290, Issue 1, 58-65, July 1999
School of Pharmacy and Pharmaceutical Sciences, University
of Manchester, Manchester, United Kingdom
The metabolism of a number of compounds by the cytochrome P-450
subfamily CYP3A does not exhibit classic Michaelis-Menten kinetics but
displays a sigmoidal rate-substrate concentration relationship.
Intrinsic clearance (CLint) cannot be calculated for these
drugs due to the lack of a first order region in their kinetic
profiles, and a suitable parameter has yet to be identified to allow
such data to be scaled to predict in vivo clearance. As sigmoidal
kinetics have only been observed with microsomal systems, we have
investigated whether this behavior is demonstrable in freshly isolated
hepatocytes. We have also evaluated the term maximum clearance
(CLmax), which refers to the in vitro clearance when the
enzyme is fully activated, to predict in vivo clearance. To these ends
we have studied the metabolism of dextromethorphan to methoxymorphinan
and dextrorphan; methoxymorphinan production is best described by
sigmoidal kinetics in both hepatocytes and microsomes, dextrorphan
production is best described by a two site Michaelis-Menten model in
microsomes but is sigmoidal in hepatocytes. Total clearance, estimated
from the CLmax and CLint terms, was scaled to
give mean predictions of 127 to 319 ml/min/standard rat weight of
250 g. In vivo CLint, determined after infusion via the hepatic portal vein to steady state and correcting for plasma
protein binding and blood-to-plasma concentration ratio, was 259 ± 59.2 ml/min/standard rat weight of 250 g. These investigations show that sigmoidal kinetics is not unique to microsomes and that CLmax is a useful parameter for scaling to the in vivo situation.
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