Received for publication December 13, 2005.
Revised June 9, 2006.
Accepted for publication June 12, 2006.

3,4-DEHYDRODEBRISOQUINE, A NOVEL DEBRISOQUINE METABOLITE FORMED FROM 4-HYDROXYDEBRISOQUINE THAT IMPACTS THE CYP2D6 METABOLIC RATIO

Abstract

Considerable unexplained inter-subject 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 (EMs) and four CYP2D6*4 homozygotes (PMs) took 12.8 mg debrisoquine hemisulfate by mouth and collected 0-8 and 8-24 h urines, which were analyzed by GCMS before and after treatment with -glucuronidase. Authentic 3,4-dehydrodebrisoquine was synthesized and characterized by GCMS, LC-MS/MS and ¹H NMR. 3,4-Dehydrodebrisoquine is a novel metabolite of debrisoquine excreted variably in 0-24 h urine, both in EMs (3.1-27.6% dose) and PMs (0-2.1% 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 4-hydroxydebrisoquine orally and also excreted 3,4-dehydrodebrisoquine. EMs excreted 6-hydroxydebrisoquine (0-4.8%), 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-hydroxy-debrisoquine 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.

Key words: CYP2D, cytochrome P450, GC/MS, glucuronidation, HPLC, human CYP enzymes, pharmacogenetics

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