Differential effects of quinidine on the disposition of nifedipine, sparteine, and mephenytoin in humans.
The effects of quinidine on oxidative routes of drug metabolism mediated by different forms of cytochrome P450 were investigated in 10 healthy subjects. Each subject was studied on three different occasions and separately received oral administration of (1) a "cocktail" of nifedipine (5 mg), sparteine sulfate (90 mg), and mephenytoin (100 mg), (2) quinidine sulfate (200 mg), and (3) quinidine sulfate followed by the "cocktail" 1 hour later. Quinidine pretreatment significantly inhibited the aromatization of nifedipine to its major first-pass pyridine metabolite (M-0) and prolonged the elimination half-life of the calcium channel antagonist, both by about 40%. More marked inhibition of metabolism was observed with sparteine, and the formation of dehydrosparteine was abolished. A significant correlation was found between the 0-8-hour urinary ratio and the plasma concentration ratio of sparteine to dehydrosparteine obtained 4 hours after drug administration. No quinidine-induced changes were observed in the 4-hydroxylation of mephenytoin. The interaction between quinidine and nifedipine supports the involvement of a common P450 (P450IIIA4) in the metabolism of the two drugs.
Division of Pharmacology, University of Leiden, The Netherlands.
J H
JH
Schellens
H
H
Ghabrial
H H
HH
van der Wart
E N
EN
Bakker
G R
GR
Wilkinson
D D
DD
Breimer
D000284:Administration, Oral; D000328:Adult; D002849:Chromatography, Gas; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008617:Mephenytoin / Q000378:metabolism / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate; D009543:Nifedipine / Q000378:metabolism / Q000493:pharmacokinetics*; D011802:Quinidine / Q000494:pharmacology*; D013034:Sparteine / Q000378:metabolism / Q000493:pharmacokinetics*
D013034:Sparteine; D009543:Nifedipine; D011802:Quinidine; D008617:Mephenytoin