Interaction of diclofenac and quinidine in monkeys: stimulation of diclofenac metabolism.
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 K(m) value for the CYP-mediated conversion of diclofenac to its 5-hydroxy derivatives was little changed (75 versus 59 microM), whereas V(max) 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.
Tang
W
W
Department of Drug Metabolism, Merck Research Laboratories, Rahway, New Jersey 07065, USA. wei_tang@merck.com
Stearns
R A
RA
Kwei
G Y
GY
Iliff
S A
SA
Miller
R R
RR
Egan
M A
MA
Yu
N X
NX
Dean
D C
DC
Kumar
S
S
Shou
M
M
Lin
J H
JH
Baillie
T A
TA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D000962:Antimalarials / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D002853:Chromatography, Liquid; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004008:Diclofenac / Q000493:pharmacokinetics*; D004347:Drug Interactions; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D011802:Quinidine / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000962:Antimalarials; D001798:Blood Proteins; D004008:Diclofenac; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D011802:Quinidine