Quinidine Diclofenac

Damkier P, Hansen LL, Brosen K. Effect of diclofenac, disulfiram, itraconazole, grapefruit juice and erythromycin on the pharmacokinetics of quinidine. Br J Clin Pharmacol 1999 48(6) 829-838. 

Tang W, Stearns RA, Kwei GY, et al. Interaction of diclofenac and quinidine in monkeys stimulation of diclofenac metabolism. J Pharmacol Exp Ther 1999 291 (3) 1068-1074. 

Ngui JS, Tang W, Steams RA, et al. Cytochrome P450 3A4-mediated interaction of diclofenac and quinidine. Dmg Metab Dispos 2000 28 1043-1050. 

Masubuchi Y, Ose A, Horie T. Diclofenac-induced inactivation of CYP3A4 and its stimulation by quinidine. Drug Metab Dispos 2002 30(10) 1143-1148. 

In human liver microsomes, diclofenac inhibited testosterone 6-beta-hydroxylation with characteristics that suggested that it inactivated CYP3A4 (76). Quinidine, which stimulates CYP3A4-mediated diclofenac 5-hydro-xylation, did not affect the inactivation of CYP3A4 assessed by testosterone 6-beta-hydroxylation activity but accelerated the inactivation assessed by diazepam 3-hydroxylation activity. 

In 30 healthy young men the pharmacokinetics of a single oral dose of quinidine 200 mg were studied before and during the daily administration of diclofenac 100 mg (a substrate of CYP2C9) (63). The clearance of quinidine by A-oxidation was reduced by diclofenac, but only by 27%. This small effect of diclofenac suggests a minor role for CYP2C9 in the metabolism of quinidine. 

A second example of in vivo activation of drug metabolism was recently reported by Wei Tang and his associates (83). The in vitro addition of quinidine to monkey liver microsomes or hepatocytes stimulated the cytochrome P450 3A4-mediated metabolism of diclofenac to 5-hydroxydiclofenac (83). Although quinidine had little or no effect on the Km for diclofenac metabolism by monkey... 

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