Disposition of debrisoquine in Caucasians with different CYP2D6-genotypes including those with multiple genes

Debrisoquine is a major prototypic in-vivo probe used to assess polymorphic CYP2D6 activity in humans, based on the 0-8 h urinary excretion of unchang ed drug and its 4-hydroxy metabolite (the so-called metabolic ratio). The p rimary purpose of the study was to investigate further the relationship bet ween genotype and phenotype by determining the overall disposition characte ristics of the drug in selected groups of healthy Swedish Caucasian individ uals. Debrisoquine (20 mg) was orally administered to five poor metabolizer s with no functional CYP2D6 gene, five heterozygous extensive metabolizers, five homozygous extensive metabolizers, five ultrarapid metabolizers with duplicated/triplicated CYP2D6*2 genes and one individual with 13 copies of CYP2D6*2. Peak plasma levels of debrisoquine and 4-hydroxydebrisoquine were attained within 2-4 h and then declined in a multi-exponential fashion ove r 96 h, However, the post 8-h period of the elimination process was charact erized by irregular fluctuations that prevented formal pharmacokinetic anal ysis. Nevertheless, marked differences were apparent in the compounds' plas ma level-time profiles between the CYP2D6 genotypes. For example, in the ca se of debrisoquine, the mean ratio of the AUC(0-8) values was 22:22:7:6:1, corresponding to 0, 1, 2, 3/4 and 13 genes and, for 4-hydroxydebrisoquine, the respective values were 1:7:19:28:17. The 0-96 h urinary recovery of deb risoquine differed 100-fold between the genotypes, being essentially comple te in poor metabolizers and zero in the individual with 13 CYP2D6*2 genes. 4-hydroxydebrisoquine excretion increased according to the number of functi onal CYP2D6 genes. A highly significant correlation (r(s) = 0.95, P < 0.001 ) was observed between the plasma AUC(0-8) ratio for debrisoquine to 4-hydr oxydebrisoquine and the 0-8 h urinary metabolic ratio. This study demonstra tes that the number of functional CYP2D6 alleles is critically important in the plasma concentration-time curves of debrisoquine and its CYP2D6-mediat ed 4-hydroxy metabolite. Concentration-related pharmacologic effects would be expected to be similarly affected by gene dosage and it is likely that t he same situation also apples to other drugs whose elimination is important ly determined by this enzyme; for example, many antidepressants and neurole ptics, antiarrhythmic agents, beta-adrenoceptor antagonists and opiates. Ph armacogenetics 9:697-706 (C) 1999 Lippincott Williams & Wilkins.