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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Rebsamen, M. C. Rossier, M. F. Samer, C. F. Hochstrasser, D. Daali, Y. Eap, C. B. Desmeules, J. A. Hopfgartner, G. Wagner, M. Dayer, P. |
| Description | Author Affiliation: Samer CF ( Clinical Pharmacology and Toxicology and Multidisciplinary Pain Centre, Department of Anaesthesiology, Pharmacology and Intensive Care, Geneva University Hospitals, Geneva, Switzerland. Caroline.Samer@hcuge.ch) |
| Abstract | BACKGROUND AND PURPOSE: The major drug-metabolizing enzymes for the oxidation of oxycodone are CYP2D6 and CYP3A. A high interindividual variability in the activity of these enzymes because of genetic polymorphisms and/or drug-drug interactions is well established. The possible role of an active metabolite in the pharmacodynamics of oxycodone has been questioned and the importance of CYP3A-mediated effects on the pharmacokinetics and pharmacodynamics of oxycodone has been poorly explored. EXPERIMENTAL APPROACH: We conducted a randomized crossover (five arms) double-blind placebo-controlled study in 10 healthy volunteers genotyped for CYP2D6. Oral oxycodone (0.2 mg x kg(-1)) was given alone or after inhibition of CYP2D6 (with quinidine) and/or of CYP3A (with ketoconazole). Experimental pain (cold pressor test, electrical stimulation, thermode), pupil size, psychomotor effects and toxicity were assessed. KEY RESULTS: CYP2D6 activity was correlated with oxycodone experimental pain assessment. CYP2D6 ultra-rapid metabolizers experienced increased pharmacodynamic effects, whereas cold pressor test and pupil size were unchanged in CYP2D6 poor metabolizers, relative to extensive metabolizers. CYP2D6 blockade reduced subjective pain threshold (SPT) for oxycodone by 30% and the response was similar to placebo. CYP3A4 blockade had a major effect on all pharmacodynamic assessments and SPT increased by 15%. Oxymorphone C(max) was correlated with SPT assessment (rho(S)= 0.7) and the only independent positive predictor of SPT. Side-effects were observed after CYP3A4 blockade and/or in CYP2D6 ultra-rapid metabolizers. CONCLUSIONS AND IMPLICATIONS: The modulation of CYP2D6 and CYP3A activities had clear effects on oxycodone pharmacodynamics and these effects were dependent on CYP2D6 genetic polymorphism. |
| ISSN | 00071188 |
| e-ISSN | 14765381 |
| Journal | British Journal of Pharmacology |
| Issue Number | 4 |
| Volume Number | 160 |
| Language | English |
| Publisher | Wiley Online Library(on behalf of The British Pharmacological Society) |
| Publisher Date | 2010-06-01 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Analgesics, Opioid Therapeutic Use Cytochrome P-450 CYP2D6 Genetics Metabolism Cytochrome P-450 CYP3A Oxycodone Adverse Effects Polymorphism, Genetic Pharmacokinetics Pharmacology Cross-Over Studies Cytochrome P-450 CYP2D6 Inhibitors Cytochrome P-450 CYP3A Inhibitors Double-Blind Method Drug Interactions Enzyme Inhibitors Genotype Metabolic Detoxication, Phase I Oxymorphone Blood Pain Threshold Drug Effects Phenotype Psychomotor Performance Reflex, Pupillary Clinical Trial Randomized Controlled Trial |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology |
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