Zhen, Yueying; Slanar, Ondrej; Krausz, Kristopher W; Chen, Chi; Slavík, Josef; McPhail, Kerry L; Zabriskie, T Mark; Perlík, Frantisek; Gonzalez, Frank J; Idle, Jeffrey R (2006). 3,4-Dehydrodebrisoquine, a novel debrisoquine metabolite formed from 4-hydroxydebrisoquine that affects the CYP2D6 metabolic ratio. Drug metabolism and disposition, 34(9), pp. 1563-74. Bethesda, Md.: American Society for Pharmacology and Experimental Therapeutics 10.1124/dmd.105.008920
Full text not available from this repository.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 beta-glucuronidase. Authentic 3,4-dehydrodebrisoquine was synthesized and characterized by GCMS, liquid chromatography-tandem mass spectrometry, and (1)H 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.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Service Sector > Institute of Clinical Pharmacology and Visceral Research [discontinued] |
UniBE Contributor: |
Idle, Jeffrey |
ISSN: |
0090-9556 |
ISBN: |
16782768 |
Publisher: |
American Society for Pharmacology and Experimental Therapeutics |
Language: |
English |
Submitter: |
Factscience Import |
Date Deposited: |
04 Oct 2013 14:45 |
Last Modified: |
05 Dec 2022 14:14 |
Publisher DOI: |
10.1124/dmd.105.008920 |
PubMed ID: |
16782768 |
Web of Science ID: |
000239938500019 |
URI: |
https://boris.unibe.ch/id/eprint/18584 (FactScience: 779) |