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Vol. 291, Issue 3, 1068-1074, December 1999
Department of Drug Metabolism (W.T., R.A.S., G.Y.K., R.R.M.,
M.A.E., N.X.Y., D.C.D., S.K., T.A.B.) and Laboratory Animal Resources
(S.A.I.), Merck Research Laboratories, Rahway, New Jersey; and
Department of Drug Metabolism (M.S., J.H.L., T.A.B.), Merck Research
Laboratories, West Point, Pennsylvania
The cytochrome P-450 (CYP)3A4-mediated metabolism of diclofenac is
stimulated in vitro by quinidine. A similar effect is observed in
incubations with monkey liver microsomes. We describe an in vivo
interaction of diclofenac and quinidine that leads to enhanced clearance of diclofenac in monkeys. After a dose of diclofenac via
portal vein infusion at 0.055 mg/kg/h, steady-state systemic plasma
drug concentrations in three male rhesus monkeys were 87, 104, and 32 ng/ml, respectively (control). When diclofenac was coadministered with
quinidine (0.25 mg/kg/h) via the same route, the corresponding plasma
diclofenac concentrations were 50, 59, and 18 ng/ml, representing 57, 56, and 56% of control values, respectively. In contrast, steady-state
systemic diclofenac concentrations in the same three monkeys were
elevated 1.4 to 2.5 times when the monkeys were pretreated with
L-754,394 (10 mg/kg i.v.), an inhibitor of CYP3A. Further investigation
indicated that the plasma protein binding (>99%) and
blood/plasma ratio (0.7) of diclofenac remained unchanged in the
presence of quinidine. Therefore, the decreases in plasma
concentrations of diclofenac after a combined dose of diclofenac and
quinidine are taken to reflect increased hepatic clearance of the drug,
presumably resulting from the stimulation of CYP3A-catalyzed oxidative
metabolism. Consistent with this proposed mechanism, a 2-fold increase
in the formation of 5-hydroxydiclofenac derivatives was observed in
monkey hepatocyte suspensions containing diclofenac and quinidine.
Stimulation of diclofenac metabolism by quinidine was diminished when
monkey liver microsomes were pretreated with antibodies against CYP3A.
Subsequent kinetic studies indicated that the
Km value for the CYP-mediated conversion of diclofenac to its 5-hydroxy derivatives was little changed (75 versus
59 µM), whereas Vmax increased 2.5-fold in
the presence of quinidine. These data suggest that the catalytic
capacity of monkey hepatic CYP3A toward diclofenac metabolism is
enhanced by quinidine.
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