Differential effects of quinidine on the disposition of nifedipine, sparteine, and mephenytoin in humans

Abstract

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. (CLIN PHARMACOL THER The rate of drug oxidation in humans often exhibits pronounced interindividual variability that is related to the activities of various cytochrome P450 enzymes. In recent years, a number of different forms of this monooxygenase have been purified and characterized at the biochemical and molecular levels.' However, a major problem exists in vivo, namely, the identification of which specific form(s) of P450 is involved in the metabolism of a particular drug and the relative contribution of each in the overall process. Several approaches have been taken to resolve this problem, including the use of model substrates administered either individually or as a "cocktail" containing several

Inhibition of debrisoquine hydroxylation with quinidine in subjects with three or more functional CYP2D6 genes

“…Although this observation is based on very few samples and thus not conclusive, it suggests that there may be a relationship between the CYP2D6 genotype and the metabolizm of quinidine. Earlier studies have indicated that although quinidine is a potent inhibitor of CYP2D6 [11–15], it is not a substrate of this enzyme [11, 30–34]. These results are, however, based on data using higher quinidine doses and concentrations than those used in the present study.…”

“…CYP2D6 is a high‐affinity, low capacity enzyme and is saturated at relatively low substrate concentrations. Thus, we cannot exclude that at low quinidine doses/concentrations, CYP2D6 may play a significant role in the metabolism of quinidine, whereas at higher quinidine levels CYP3A4 might become the predominant enzyme [11, 32]. Further studies are required to establish if CYP2D6 is involved in the metabolizm of quinidine at low doses and concentrations of the drug.…”

“…The therapeutic oral dose is 0.8–2.0 g day −1 and the therapeutic plasma concentration is 4–12 μmol l −1 [9]. Renal elimination of unchanged drug accounts for 15–40% of ingested dose and 3‐hydroxylation and N ‐oxidation by CYP3A4 account for the remaining part of the elimination [10, 11]. Quinidine is a potent inhibitor of CYP2D6 [12–15].…”

The karolinska cocktail for phenotyping of five human cytochrome P450 enzymes

“…A cocktail design offers several advantages through the required knowledge of drug metabolic pathways obtained in a single experimental session involving possible pharmacologic or pathophysiologic effects on enzyme induction or inhibition. Effects such as concomitant drug therapy and liver disease have been evaluated with the use of several different cocktails 2 , 3 , 4 , 5 . Another advantage with a cocktail is that environmental factors do not change during the limited time of the experiment 1 .…”

Unexpected interaction between CYP3A4 and BI 11634: is BI 11634 interacting with CYP3A4 similar to nifedipine?

“…Clinically relevant DDIs have been observed between quinidine and nifedipine. In two studies, nifedipine exposure (AUC 0-8h ) increased 37% and the formation of the major metabolite decreased about 40% after administration of quinidine, which was attributed to inhibition of CYP3A4-mediated metabolism [16,17]. Therefore, it is important to have a clearer understanding of an interaction between a drug and CYP3A4 if the drug behaves similar to nifedipine.…”