RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 1563
OP 1574
DO 10.1124/dmd.105.008920
VO 34
IS 9
A1 Yueying Zhen
A1 Ondřej Slanař
A1 Kristopher W. Krausz
A1 Chi Chen
A1 Josef Slavík
A1 Kerry L. McPhail
A1 T. Mark Zabriskie
A1 František Perlík
A1 Frank J. Gonzalez
A1 Jeffrey R. Idle
YR 2006
UL http://dmd.aspetjournals.org/content/34/9/1563.abstract
AB 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