Effect of diclofenac, disulfiram, itraconazole, grapefruit juice and erythromycin on the pharmacokinetics of quinidine.
OBJECTIVE
In 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 clearance 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. Cmax 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.
Damkier
P
P
Institute of Public Health, Clinical Phamacology, University of Southern Denmark, Odense, Denmark. p-damkier@cekfo.sdu.dk
Hansen
L L
LL
Brosen
K
K
D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D001628:Beverages; D002957:Citrus / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2; D065729:Cytochrome P-450 CYP2C9; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004008:Diclofenac / Q000494:pharmacology*; D004221:Disulfiram / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004917:Erythromycin / Q000494:pharmacology*; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology*; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010084:Oxidation-Reduction; D011802:Quinidine / Q000378:metabolism / Q000493:pharmacokinetics*; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000378:metabolism
D065691:Cytochrome P-450 CYP2E1 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D004008:Diclofenac; D017964:Itraconazole; D004917:Erythromycin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C504573:CYP1A2 protein, human; C104464:CYP3A protein, human; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; D039181:Steroid 16-alpha-Hydroxylase; C510163:CYP3A4 protein, human; D011802:Quinidine; D004221:Disulfiram