| Inhibition of debrisoquin clearance in perfused rat livers and inhibition of dextromethorphan metabolism in human liver microsomes by 4-hydroxydebrisoquin or other metabolites of debrisoquin. | |
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MedLine Citation:
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PMID: 1355711 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Debrisoquin undergoes oxidative metabolism to 4-hydroxydebrisoquin, catalyzed by cytochrome CYP2D1 in rats and CYP2D6 in humans. Cytochrome CYP2D6 also plays a major role in dextromethorphan O-demethylation. In preliminary studies in perfused Lewis rat livers, we observed a difference in repeat clearance experiments using debrisoquin, but not dextromethorphan. To determine whether this change in clearance with time was due to the accumulation of 4-hydroxydebrisoquin, we sequentially used a recirculating and nonrecirculating perfusion system in the same liver perfusion experiment. We also studied the kinetics of dextromethorphan O-demethylation in microsomes prepared from human and rat livers in the presence and absence of 4-hydroxydebrisoquin. Results from the perfused rat liver experiments showed a drop in clearance from 3.27 +/- 0.57 ml/min (clearance 1) to 1.61 +/- 0.27 ml/min (clearance 2) (p less than 0.05 vs. clearance 1) during recirculation, but clearance returned to 3.21 +/- 0.46 ml/min (clearance 3, no significance vs. clearance 1) after a 30-min period of liver perfusion using a nonrecirculating system. There was significant accumulation of 4-hydroxydebrisoquin in the liver perfusate during recirculation, and concentrations fell when the nonrecirculating system was used. In microsomal studies, 4-hydroxydebrisoquin competitively inhibited dextromethorphan metabolism in human microsomes was 600 microM. These data suggest that: (a) 4-hydroxydebrisoquin and/or other metabolites of debrisoquin have an inhibitory effect on CYP2D1 and CYP2D6; (b) the active site of human CYP2D6 has different substrate specificity than the rat isozyme (CYP2D1) and/or that the pathways of metabolism of dextromethorphan are different in the Lewis rat and not primarily dependent on the activity of CYP2D1. |
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Authors:
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S Jaruratanasirikul; A D Cooper; T F Blaschke |
Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Drug metabolism and disposition: the biological fate of chemicals Volume: 20 ISSN: 0090-9556 ISO Abbreviation: Drug Metab. Dispos. Publication Date: 1992 May-Jun |
Date Detail:
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Created Date: 1992-10-15 Completed Date: 1992-10-15 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 9421550 Medline TA: Drug Metab Dispos Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 379-82 Citation Subset: IM |
Affiliation:
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Department of Medicine, Stanford University Medical Center, CA 94305-5113. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cytochrome P-450 CYP2D6 Cytochrome P-450 Enzyme System / metabolism Debrisoquin / analogs & derivatives*, metabolism*, pharmacology Dextromethorphan / metabolism* Female Humans Liver / metabolism* Methylation Microsomes, Liver / metabolism* Mixed Function Oxygenases / metabolism Rats Rats, Inbred Lew Substrate Specificity |
| Grant Support | |
ID/Acronym/Agency:
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AI27762/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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1131-64-2/Debrisoquin; 125-71-3/Dextromethorphan; 59333-79-8/4-hydroxydebrisoquin; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.-/Mixed Function Oxygenases; EC 1.14.14.1/Cytochrome P-450 CYP2D6 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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