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https://hdl.handle.net/2440/14589
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Type: | Journal article |
Title: | CYP3A4 mediates dextropropoxyphene N-demethylation to nordextropropoxyphene: human in vitro and in vivo studies and lack of CYP2D6 involvement |
Author: | Somogyi, A. Menelaou, A. Fullston, S. |
Citation: | Xenobiotica: the fate of foreign compounds in biological systems, 2004; 34(10):875-887 |
Publisher: | Taylor & Francis Ltd |
Issue Date: | 2004 |
ISSN: | 0049-8254 1366-5928 |
Statement of Responsibility: | A. A. Somogyi, A. Menelaou and S. V. Fullston |
Abstract: | 1. The individual cytochrome P450 isoforms in dextropropoxyphene N-demethylation to nordextropropoxyphene were determined and the pharmacokinetics of dextropropoxyphene and nordextropropoxyphene in cytochrome P4502D6 (CYP2D6) extensive (EM) and poor (PM) subjects were characterized. 2. Microsomes from six CYP2D6 extensive metabolizers and one CYP2D6 poor metabolizer were used with isoform specific chemical and antibody inhibitors and expressed recombinant CYP enzymes. Groups of three CYP2D6 EM and PM subjects received a single 65-mg oral dose of dextropropoxyphene, and blood and urine were collected for 168 and 96 h, respectively. 3. Nordextropropoxyphene formation in vitro was not different between the CYP2D6 extensive metabolizers (Km = 179 ± 74 M, Clint = 0.41 ± 0.26 ml mg-1 h-1) and the PM subject (Km = 225 M, Clint = 0.19 ml mg-1 h-1) and was catalysed predominantly by CYP3A4. There was no apparent difference in the pharmacokinetics of dextropropoxyphene and nordextropropoxyphene in CYP2D6 EM and PM subjects. 4. CYP3A4 is the major CYP enzyme catalysing the major metabolic pathway of dextropropoxyphene metabolism. Hence variability in the pharmacodynamic effects of dextropropoxyphene are likely due to intersubject variability in hepatic CYP3A4 expression and/or drug-drug interactions. Reported CYP2D6 phenocopying is not due to dextropropoxyphene being a CYP2D6 substrate. |
Keywords: | Cells, Cultured Microsomes, Liver Humans Cytochrome P-450 Enzyme System Cytochrome P-450 CYP2D6 Metabolic Clearance Rate Administration, Oral Methylation Phenotype Adult Aged Middle Aged Female Male Cytochrome P-450 CYP3A Dextropropoxyphene |
Rights: | © Taylor & Francis |
DOI: | 10.1080/00498250400008371 |
Published version: | http://dx.doi.org/10.1080/00498250400008371 |
Appears in Collections: | Aurora harvest 7 Pharmacology publications |
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