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Vol. 26, Issue 6, 552-561, June 1998
Department of Pharmacology, The Ohio State University (T.K., E.I.,
I.U., E.S., D.O., J.M., N.G.), and
Department of Chemistry,
Northeastern University (E.G., P.V.)
Both ritonavir and indinavir were readily metabolized by human
intestinal microsomes. Comparison of the patterns of metabolites in
incubations with enterocyte microsomes and expressed cytochrome P450
(CYP) isozymes and immunoinhibition and chemical inhibition studies
showed the essential role of the CYP3A subfamily in the metabolism of
both protease inhibitors by the small intestine. Ritonavir was
similarly biotransformed by microsomes containing expressed CYP3A4 or
CYP3A5 isozymes (KM = 0.05-0.07 µM,
Vmax = 1-1.4 nmol/min/nmol CYP). In
contrast, both the patterns of metabolites and the enzyme kinetic
parameters for the metabolism of indinavir by expressed CYP3A5
(KM = 0.21 µM,
Vmax = 0.24 nmol/min/nmol CYP) and CYP3A4
(KM = 0.04 µM,
Vmax = 0.68 nmol/min/nmol CYP) were different. The biotransformation of both indinavir and ritonavir in
human enterocyte microsomes was characterized by very low
KM values (0.2-0.4 µM for indinavir
and <0.1 µM for ritonavir). The Vmax
for indinavir metabolism was greater in enterocyte (163 ± 35 pmol/min/mg protein) than in liver (68 ± 44 pmol/min/mg protein) microsomes. The metabolism of ritonavir in liver and enterocyte microsomes was associated with inactivation of CYP3A. The initial Vmax for ritonavir metabolism by
enterocyte microsomes was 89 ± 59 pmol/min/mg protein. The
apparent inactivation rate constants for intestinal CYP3A and expressed
CYP3A4 were 0.078 and 0.135 min
1,
respectively. Metabolic inactivation of CYP3A by ritonavir explains the
improved bioavailability and pharmacokinetics of ritonavir and the
sustained elevation of blood levels of other, concomitantly administered, substrates of CYP3A.
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