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

Aims To study whether the CYP2D6 capacity in ultrarapid metabolizers of deb risoquine due to duplication/multiduplication of a functional CYP2D6 gene, can be 'normalised' by low doses of the CYP2D6 inhibitor quinidine and whet her this is dose-dependent. Methods Five ultrarapid metabolizers of debrisoquine with 3, 4 or 13 functi onal 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 gi ven. Urine was collected for 6 h after debrisoquine administration. Debriso quine and its 4-hydroxymetabolite were analysed by h.p.l.c. and the debriso quine metabolic ratio (MR) was calculated. Results Without quinidine the MR in the ultrarapid metabolizers ranged betw een 0.01 and 0.07. A dose-effect relationship could be established for quin idine 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 requi red 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 i nhibition of CYP2D6 in ultrarapid metabolizers. The clinical use of low dos es 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' ca used by ultrarapid metabolism.