Effect of diclofenac, disulfiram, itraconazole, grapefruit juice and erythromycin on the pharmacokinetics of quinidine

Aims In vitro studies suggest that the oxidation of quinidine to 3-hydroxyq uinidine is a specific marker reaction for CYP3A4 activity. To assess the p ossible use of this reaction as an in vivo marker of CYP3A4 activity, we st udied the involvement of cytochromes CYP2C9, CYP2E1 and CYP3A4 in the in vi vo oxidative metabolism of quinidine. Methods An open study of 30 healthy young male volunteers was performed. Th e pharmacokinetics of a 200 mg single oral dose of quinidine was studied be fore and during daily administration of 100 mg diclofenac, a CYP2C9 substra te (n = 6); 200 mg disulfiram, an inhibitor of CYP2E1 (n = 6); 100 mg itrac onazole, an inhibitor of CYP3A4 (n = 6); 250 ml single strength grapefruit juice twice daily, an inhibitor of CYP3A4 (n = 6); 250 mg of erythromycin 4 times daily, an inhibitor of CYP3A4 (n = 6). Probes of other enzyme activi ties, caffeine (CYP1A2), sparteine (CYP2D6), mephenytoin (CYP2C19), tolbuta mide (CYP2C9) and cortisol (CYP3A4) were also studied. Results Concomitant administration of diclofenac reduced the partial cleara nce of quinidine by N-oxidation by 27%, while no effect was found for other pharmacokinetic parameters of quinidine. Concomitant administration of dis ulfiram did not alter any of the pharmacokinetic parameters of quinidine. C oncomitant administration of itraconazole reduced quinidine total clearance , partial clearance by 3-hydroxylation and partial clearance by N-oxidation by 61, 84 and 73%, respectively. The renal clerance was reduced by 60% and the elimination half-life increased by 35%. Concomitant administration of grapefruit juice reduced the total clearance of quinidine and its partial c learance by 3-hydroxylation and N-oxidation by 15, 19 and 27%, respectively . The elimination half-life of quinidine was increased by 19%. The caffeine metabolic index was reduced by 25%. Concomitant administration of erythrom ycin reduced the total clearance of quinidine and its partial clearance by 3-hydroxylation and N-oxidation by 34, 50 and 33%, respectively. C-max was increased by 39%. Conclusions The results confirm an important role for CYP3A4 in the oxidati on of quinidine in vivo, and this applies particularly to the formation of 3-hydroxyquinidine. While a minor contribution of CYP2C9 to the N-oxidation of quinidine is possible, a major involvement of the CYP2C9 or CYP2E1 enzy mes in the oxidation of quinidine in vivo is unlikely.