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

Abstract

AimsIn vitro studies suggest that the oxidation of quinidine to 3-hydroxyquinidine is a specific marker reaction for CYP3A4 activity. To assess the possible use of this reaction as an in vivo marker of CYP3A4 activity, we studied the involvement of cytochromes CYP2C9, CYP2E1 and CYP3A4 in the in vivo oxidative metabolism of quinidine. Methods An open study of 30 healthy young male volunteers was performed. The pharmacokinetics of a 200 mg single oral dose of quinidine was studied before and during daily administration of 100 mg diclofenac, a CYP2C9 substrate (n=6); 200 mg disulfiram, an inhibitor of CYP2E1 (n=6); 100 mg itraconazole, 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 activities, caffeine (CYP1A2), sparteine (CYP2D6), mephenytoin (CYP2C19), tolbutamide (CYP2C9) and cortisol (CYP3A4) were also studied. Results Concomitant administration of diclofenac reduced the partial clearance of quinidine by N-oxidation by 27%, while no effect was found for other pharmacokinetic parameters of quinidine. Concomitant administration of disulfiram did not alter any of the pharmacokinetic parameters of quinidine. Concomitant 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 clearance 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 erythromycin 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 oxidation 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 enzymes in the oxidation of quinidine in vivo is unlikely.

Effect of sodium diclofenac on the bioavailability of amoxicillin

“…Diclofenac was observed to reduce the partial clearance of quinidine through N-oxidation when they were administered concomitantly [34]. Another study showed that diclofenac produced non-competitive inhibition of codeine glucuronidation, considered important to the formation of the codeine-6-glucuronide metabolite [35].…”

Drug–drug interactions of antifungal agents and implications for patient care

“…The resultant increases in serum digoxin concentrations produce symptomatic toxicity and necessitated 60 -75% reductions in digoxin doses to achieve safe and effective concentrations [89,90]. ITZ also interacts with quinidine through both CYP-and P-gp-mediated processes [91][92][93].…”

Drug-Drug Interactions via Mechanism-Based Cytochrome P450 Inactivation: Points to Consider for Risk Assessment from In Vitro Data and Clinical Pharmacologic Evaluation

“…To illustrate the above discussed concepts, in vitro inactivation kinetic parameter estimates were compiled for 14 representative drugs that have been kinetically characterized for CYP inactivation in vitro and also tested in clinical drug-drug interaction studies with substrates of CYP1A2 [4,23], CYP2B6 [7], CYP2C19 [9], CYP2D6 [24] or CYP3A [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44]. In vitro kinetic parameters (k inact and K I ) for CYP1A2 inactivation by zileuton [5] and oltipraz [45], CYP2B6 [6] and CYP2C19 [8] inactivation by ticlopidine, CYP2D6 inactivation by paroxetine [15], and CYP3A inactivation by ethinyl estradiol [46], diclofenac [47], azithromycin [48,49], fluoxetine [18,50,51], erythromycin [48,49,[52][53][54], diltiazem [55,56], racemic verapamil [50,…”