The role of genetic polymorphism in the oxidative metabolism of metoprolol and debrisoquin was investigated in a population of 138 unrelated Nigerians. The debrisoquin/4-hydroxydebrisoquin 0-8 hour urinary ratio (D/HD) correlated significantly with the metoprolol/alpha-hydroxymetoprolol 0-8 hour urinary ratio (M/HM) (rs = 0.54; P less than 0.001), the metoprolol/H117-04 [4-(2-hydroxy-3-isopropylaminopropoxy)-phenylacetic acid] 0-8 hour urinary ratio (M/H117-04) (rs = 0.42; P less than 0.001), and the plasma metoprolol concentration at 3 hours (rs = 0.48; P less than 0.01). Both the median D/HD and M/HM ratios were significantly higher in this population than in a previously studied population of white British subjects. According to criteria established in studies of white populations, only one subject, later identified as an Indian, would be classified unequivocally as a poor metabolizer of both metoprolol and debrisoquin. All the other subjects were black Africans. Bimodality in the frequency distribution of both the log10 M/HM and D/HD ratios was not apparent. The poor hydroxylation trait may, therefore, be present at a lower frequency than in whites, absent altogether, or obscured by other factors. In ethnic studies of drug metabolism each racial group should be examined separately for evidence of polymorphic metabolism and antimodes should not be extrapolated from one population to another.
Download full-text PDF |
Source |
---|---|
http://dx.doi.org/10.1038/clpt.1986.195 | DOI Listing |
Mol Pharmacol
April 2015
Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (C.J.H., L.A.M., C.R.W.), TaconicArtemis, Cologne, Germany (N.S.); and Consultant in Investigative Toxicology, Linlithgow, United Kingdom (L.A.S.)
The cytochrome P450-dependent mono-oxygenase system is responsible for the metabolism and disposition of chemopreventive agents, chemical toxins and carcinogens, and >80% of therapeutic drugs. Cytochrome P450 (P450) activity is regulated transcriptionally and by the rate of electron transfer from P450 reductase. In vitro studies have demonstrated that cytochrome b5 (Cyb5) also modulates P450 function.
View Article and Find Full Text PDFDrug Metab Dispos
January 2012
Pharmacokinetics and Drug Metabolism, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98119, USA.
Predicting the magnitude of potential drug-drug interactions is important for underwriting patient safety in the clinical setting. Substrate-dependent inhibition of cytochrome P450 enzymes may confound extrapolation of in vitro results to the in vivo situation. However, the potential for substrate-dependent inhibition with CYP2D6 has not been well characterized.
View Article and Find Full Text PDFDrug Metab Pharmacokinet
October 2010
Drug Metabolism & Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co. Ltd., Shinagawa R&D Center, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, japan.
Cytochrome P450 2D6 (CYP2D6) is an enzyme with a large interindividual variability in its metabolic activity due to genetic polymorphisms. In the present study, both its intrinsic metabolic activity (CL(int,CYP2D6,app)) relative to extensive metabolizers (EM) and its variability were estimated by analyzing the urinary metabolic ratios (MR) based on the well-stirred model. Sparteine and debrisoquine were considered to be appropriate probes for our methodology, whereas dextromethorphan was not appropriate since the formation of its metabolite of interest is not described by the well-stirred model.
View Article and Find Full Text PDFEur J Clin Pharmacol
April 2007
Department of Pharmacology, Clinical Pharmacology, University of Cologne, Gleueler Strasse 24, 50931, Köln, Germany.
Introduction: Cytochrome P450 2D6 (CYP2D6) is one of the most important enzymes catalyzing biotransformation of xenobiotics in the human liver. This enzyme's activity shows a high degree of interindividual variability caused in part by its genetic polymorphism, the so-called debrisoquine/sparteine polymorphism. The genetic component influencing CYP2D6 activity can be determined by genotyping.
View Article and Find Full Text PDFJ Clin Pharmacol
December 2005
Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, SP, Brazil.
The influence of chronic renal failure on the stereoselective metabolism of rac-metoprolol was investigated in 15 hypertensive patients, 7 of them with chronic renal failure and 8 with normal renal function. They were treated with rac-metoprolol (200 mg) for 7 days. The patients of both groups presented stereoselectivity in metoprolol metabolism, favoring the formation of 1'R-alpha-hydroxymetoprolol (AUC(1(')R/1(')S)(0-24) approximately 2.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!