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

Abstract

Aims To study whether the CYP2D6 capacity in ultrarapid metabolizers of debrisoquine due to duplication/multiduplication of a functional CYP2D6 gene, can be 'normalised' by low doses of the CYP2D6 inhibitor quinidine and whether this is dose-dependent. Methods Five ultrarapid metabolizers of debrisoquine with 3, 4 or 13 functional CYP2D6 genes were given single oral doses of 5, 10, 20, 40, 80 and 160 mg quinidine. Four hours after quinidine intake, 10 mg debrisoquine was given. Urine was collected for 6 h after debrisoquine administration. Debrisoquine and its 4-hydroxymetabolite were analysed by h.p.l.c. and the debrisoquine metabolic ratio (MR) was calculated. Results Without quinidine the MR in the ultrarapid metabolizers ranged between 0.01 and 0.07. A dose-effect relationship could be established for quinidine with regard to the inhibitory effect on CYP2D6 activity. To reach an MR of 1-2, subjects with 3 or 4 functional genes required a quinidine dose of about 40 mg, while the sister and brother with 13 functional genes required about 80 mg quinidine. After 160 mg quinidine, the MRs, in the subjects with 3, 3, 4, 13 and 13 functional genes, were 12.6, 10.1, 9.2, 2.4 and 2.2, respectively. Conclusions A dose-effect relationship could be established for quinidine inhibition of CYP2D6 in ultrarapid metabolizers. The clinical use of low doses of quinidine as an inhibitor of CYP2D6 might be considered in ultrarapid metabolizers taking CYP2D6 metabolized drugs rather than giving increased doses of the drug. Normalizing the metabolic capacity of CYP2D6, by giving a low dose of quinidine, may solve the problem of 'treatment resistance' caused by ultrarapid metabolism.

4-Hydroxylation of Debrisoquine by Human CYP1A1 and Its Inhibition by Quinidine and Quinine

“…Quinidine has long been used as the cardinal specific and high-affinity inhibitor of CYP2D6. von Bahr et al (1985) first showed that quinidine was an unusually potent inhibitor (K i ϭ 0.27 M) of debrisoquine hydroxylase in vitro, using desmethylimipramine 2-hydroxylation as the probe; the isomeric quinine had a K i of 12 M. Complete inhibition of an oxidative reaction by quinidine, with a K i in the submicromolar range, has generally been taken as evidence that the reaction was mediated by CYP2D6 (Speirs et al, 1986;Otton et al, 1988;Branch et al, 2000;Dalen et al, 2000). Addition of either 0.01 to 10 M quinidine or 0.1 to 100 M quinine strongly inhibited the 4-hydroxylation of debrisoquine by CYP2D6, as anticipated, but also, unexpectedly, debrisoquine 4-hydroxylation by CYP1A1 (Fig.…”

CNVs of human genes and their implication in pharmacogenetics

“…An in vivo inhibition study of a dose-effect relationship for quinidine inhibition of debrisoquine metabolism in UMs with 3, 4, or 13 functional CYP2D6 genes showed that addition of a low dose of quinidine could, in some cases, solve the problem of treatment resistance or prevent toxicity caused by ultrarapid metabolism. This would however require further testing, if applicable, in clinical situations where steady state levels have been reached (Dalen et al, 2000). In a subsequent study it was shown that in four out of five CYP2D6 UMs it was possible to normalize nortriptyline pharmacokinetics at steady state by addition of the inhibitor paroxetine (Laine et al, 2001).…”

Drug disposition of chiral and achiral drug substrates metabolized by cytochrome P450 2D6 isozyme: case studies, analytical perspectives and developmental implications

“…While the proposed cause of ultrarapid metabolism may be due to duplication and/or multiduplication of a functional CYP2D6 gene, it was noteworthy that a low dose of quinidine was adequate to impair the metabolism of debrisoquine such that the metabolic capacity of the subjects appeared to be normalized (metabolic ratios were 0.01-0.07 prior to quindine intake and 2-13 after low-dose quinidine). An establishment of dose-effect response confirmed the feasibility of this approach (Dalen et al, 2000). The authors concluded that the use of a low dose of quinidine is a better option to correct the metabolic capacity of ultra metabolizers of CYP2D6 as opposed to increasing the doses, especially in situations of treatment resistance (Dalen et al, 2000).…”

“…The interesting work of Dalen et al (2000) provides some insights in subjects who are considered ultrarapid metabolizers of CYP2D6 (i.e. debrisoquine was the substrate).…”

“…While PMs represent an issue for variability, the presence of ultra rapid metabolizers further confounds the variability in both pharmacokinetics and dynamics. The issue of treatment failures due to ultrarapid metabolism can be addressed by slowing down the excess capacity of CYP2D6 by administration of a small dose of quinidine, a potent inhibitor of CYP2D6 (Dalen et al, 2000).…”