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Vol. 28, Issue 5, 567-572, May 2000
Department of Drug Metabolism, Merck Research Laboratories, West
Point, Pennsylvania
Acetonitrile is an organic solvent commonly used to increase
the solubility of lipophilic substrates for in vitro studies. In this
study, we examined its effect on four reactions (diclofenac hydroxylation, tolbutamide methyl hydroxylation, phenytoin
hydroxylation, and celecoxib methyl hydroxylation) catalyzed by human
liver microsomes and by the recombinant CYP2C9. In both cases, the
effect of acetonitrile on activity was found to be substrate-dependent.
Namely, it increased diclofenac 4'-hydroxylase and tolbutamide methyl
hydroxylase activities, but decreased celecoxib methyl hydroxylase
activity in a concentration-dependent manner. By comparison,
hydroxylation of phenytoin was resistant to its effect. The presence of
acetonitrile (3%, v/v) gave rise to a lower
Km and a higher
Vmax for diclofenac hydroxylase in both
liver microsomes and recombinant CYP2C9 preparations (87 and 52%
increase in
Vmax/Km ratio,
respectively). On the other hand, the inhibitory effect of the solvent
(1%, v/v) toward celecoxib hydroxylase was characterized by a decrease
in Vmax (human liver microsomes) or a change
in both Km and
Vmax (rCYP2C9), leading to 25 and 46%
decrease in
Vmax/Km for both
systems. The results of this study underscore the need for careful
evaluation of solvent effects before initiation of inhibition or
cytochrome P450 reaction phenotyping studies.
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