Background and objective: Tramadol is metabolized by the highly polymorphic enzyme cytochrome P450 (CYP)2D6. Patients with different CYP2D6 genotypes may respond differently to tramadol in terms of pain relief and adverse events. In this study, we compare the pharmacokinetics and effects of tramadol in Malaysian patients with different genotypes to establish the pharmacokinetic-pharmacodynamic relationship of tramadol.
Study design and setting: All patients received an intravenous dose of tramadol 100mg as their first postoperative analgesic. Blood was sampled at 0 minutes and subsequently at 15 and 30 minutes, 1, 2, 4, 8, 16, 20, and 24 hours for serum tramadol and analyzed by high-performance liquid chromatography (HPLC). Patients were genotyped for CYP2D6*1, *3, *4, *5, *9, *10, and *17 alleles and duplication of the gene by means of an allele-specific PCR. Pain was measured using the Visual Analog Scales, and adverse effects were recorded.
Results: About half of the patients had the wild-type allele (CYP2D6*1), with the ‘Asian’ CYP2D6* 10 allele accounting for most of the rest (40%). None of the genotypes predicted poor metabolism. Twenty-seven percent of the patients were intermediate metabolizers (IM) and 2.9% were ultra-rapid (UM) metabolizers; the remaining 70% were extensive metabolizers (EM). The mean total clearance (CL) predicted by the model was lower (19 L/h) and the half-life longer (5.9 hours) than those reported in Western populations. This may due to the high frequency of the CYP2D6*10 allele amongst Malaysian patients. The UM and EM groups had 2.6- and 1.3-times faster CL, respectively, than the IM. CL was 16, 18, 23, and 42 L/h while mean half-lives were 7.1, 6.8, 5.6, and 3.8 hours among the IM, EM1, EM2, and UM groups, respectively. However, the analgesic effects of tramadol were not measured adequately among the postoperative patients to establish its full therapeutic effects. There were significant differences in the adverse-effect profiles amongst the various genotype groups, with the IM group experiencing more adverse effects than the EM, and the EM having more adverse effects than the UM.
Conclusion: CYP2D6 activity may play an important role in determining the pharmacokinetics of tramadol and in predicting its adverse effects. If these results can be confirmed in a larger population, genotyping may be an important tool in determining the dose of tramadol.
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This study was supported, in part, by a grant from the Ministry of Science, Technology and Environment of Malaysia (MOSTI).
Tramadol for high-performance liquid chromatography (HPLC) was donated by Grünenthal, Germany. We thank Mr Tengku Azaha for his skillful technical assistance in preparing the samples and operating the HPLC system, Dr Jennie Wong of the National University of Singapore for providing a positive control for CYP2D6*5, Professor Inger Johansson of Karolinska Institutet, Sweden, for providing a positive control for CYP2D6*10, and Dr rer. nat. Ulrich Griese of the Dr Margarete Fischer-Bosch-Institut fuer Klinische Pharmakologie Auerbachstr for providing positive controls for CYP2D6*3 and *4. Special thanks to Professor Roger Jelliffe (Professor of Medicine, Laboratory of Applied Pharmacokinetics, University of Southern California, USA) for his invaluable advice on population pharmacokinetic modeling.
The authors have no conflicts of interest that are directly relevant to the content of this study.
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