Interaction of diclofenac and quinidine in monkeys: Stimulation of diclofenac metabolism

The cytochrome P-450 (CYP)3A4-mediated metabolism of diclofenac is stimulat ed in vitro by quinidine. A similar effect is observed in incubations with monkey liver microsomes. We describe an in vivo interaction of diclofenac a nd quinidine that leads to enhanced clearance of diclofenac in monkeys. Aft er a dose of diclofenac via portal vein infusion at 0.055 mg/kg/h, steady-s tate systemic plasma drug concentrations in three male rhesus monkeys were 87, 104, and 32 ng/ml, respectively (control). When diclofenac was coadmini stered 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 sy stemic 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 quini dine are taken to reflect increased hepatic clearance of the drug, presumab ly 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 suspe nsions containing diclofenac and quinidine. Stimulation of diclofenac metab olism by quinidine was diminished when monkey liver microsomes were pretrea ted with antibodies against CYP3A. Subsequent kinetic studies indicated tha t the K-m value for the CYP-mediated conversion of diclofenac to its 5-hydr oxy derivatives was little changed (75 versus 59 mu M), whereas V-max incre ased 2.5-fold in the presence of quinidine. These data suggest that the cat alytic capacity of monkey hepatic CYP3A toward diclofenac metabolism is enh anced by quinidine.