TY - JOUR T1 - 3,4-Dehydrodebrisoquine, a Novel Debrisoquine Metabolite Formed from 4-Hydroxydebrisoquine That Affects the CYP2D6 Metabolic Ratio JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1563 LP - 1574 DO - 10.1124/dmd.105.008920 VL - 34 IS - 9 AU - Yueying Zhen AU - Ondřej Slanař AU - Kristopher W. Krausz AU - Chi Chen AU - Josef Slavík AU - Kerry L. McPhail AU - T. Mark Zabriskie AU - František Perlík AU - Frank J. Gonzalez AU - Jeffrey R. Idle Y1 - 2006/09/01 UR - http://dmd.aspetjournals.org/content/34/9/1563.abstract N2 - Considerable unexplained intersubject variability in the debrisoquine metabolic ratio (urinary debrisoquine/4-hydroxydebrisoquine) exists within individual CYP2D6 genotypes. We speculated that debrisoquine was converted to as yet undisclosed metabolites. Thirteen healthy young volunteers, nine CYP2D6*1 homozygotes [extensive metabolizers (EMs)] and four CYP2D6*4 homozygotes [poor metabolizers (PMs)] took 12.8 mg of debrisoquine hemisulfate by mouth and collected 0- to 8- and 8- to 24-h urines, which were analyzed by gas chromatography-mass spectrometry (GCMS) before and after treatment with β-glucuronidase. Authentic 3,4-dehydrodebrisoquine was synthesized and characterized by GCMS, liquid chromatography-tandem mass spectrometry, and 1H NMR. 3,4-Dehydrodebrisoquine is a novel metabolite of debrisoquine excreted variably in 0- to 24-h urine, both in EMs (3.1–27.6% of dose) and PMs (0–2.1% of dose). This metabolite is produced from 4-hydroxydebrisoquine in vitro by human and rat liver microsomes. A previously unstudied CYP2D6*1 homozygote was administered 10.2 mg of 4-hydroxydebrisoquine orally and also excreted 3,4-dehydrodebrisoquine. EMs excreted 6-hydroxydebrisoquine (0–4.8%) and 8-hydroxydebrisoquine (0–1.3%), but these phenolic metabolites were not detected in PM urine. Debrisoquine and 4-hydroxydebrisoquine glucuronides were excreted in a highly genotype-dependent manner. A microsomal activity that probably does not involve cytochrome P450 participates in the further metabolism of 4-hydroxydebrisoquine, which we speculate may also lead to the formation of 1- and 3-hydroxydebrisoquine and their ring-opened products. In conclusion, this study suggests that the traditional metabolic ratio is not a true measure of the debrisoquine 4-hydroxylation capacity of an individual and thus may, in part, explain the wide intragenotype variation in metabolic ratio. The American Society for Pharmacology and Experimental Therapeutics ER -