An investigation of the clinical relevance of genetic polymorphism of CYP2D6 in the use of tramadol hydrochloride in post operative orthopaedic patients
Despite recent advances in anaesthesia, postoperative analgesia remains inadequate and is governed by many factors, one of which is pharmacogenetics. Fear of drug dependence exists with conventional opioid analgesics and there are needs for new drugs such as tramadol hydrochloride. Tramadol however,...
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| Format: | Thesis Book |
| Language: | English |
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| Summary: | Despite recent advances in anaesthesia, postoperative analgesia remains inadequate and is governed by many factors, one of which is pharmacogenetics. Fear of drug dependence exists with conventional opioid analgesics and there are needs for new drugs such as tramadol hydrochloride. Tramadol however, is metabolised by the CYP2D6 enzyme which is one of the most polymorphic enzyme systems. Tramadol was also first introduced in the Europe with dosings based on Caucasian data. Due to the wide interethnic variabilities in metabolising this drug, a pharmacogenetic-pharmacokinetics study is essential to be used as a basis for developing optimum dosage regimens of tramadol. The study was approved by the local Ethics Committees. Initially, a new HPLC method to analyse serum tramadol and O-desmethyltramadol (Ml) levels was developed and later validated. Then, PCR methods were optimised to detect the following mutations: CYP2D6*1, *3, *4, *5, *9, *10, *17, duplication and deletion gene. All patients received a 100 mg intravenous (Iv) dose of tramadol, infused over 2-3 min, as their first postoperative analgesic. Blood was sampled at 0 min and subsequently at 15 min, 30 min, 1h, 2 h, 4 h, 8 h, 16 h, 20 h and 24 h for serum tramadol HPLC analysis. NPEM2 was then used to determine population pharmacokinetic parameter values of tramadol. The developed HPLC method was selective and linear for concentrations ranging from 50 to 3500 ng/ml (tramadol) and 50 to 500 ng/ml (M1) with mean recoveries of 94.36±12.53%and 93.52±7.88% respectively. Limit of quantitation (LOQ) was 50 ng/ml. For tramadol, the intraday accuracy ranged from 95.48 to 114.64% and the interday accuracy,97.21 to 103.24%. Good precision (0.51 and 18.32% for intra and inter-day respectively) was obtained at LOQ. About half of the subjects possess the wild-type allele with the "Asian" CYP2D6* 10 coming a close second at 40.22%. Of the three null alleles determined (CYP2D6* 3, *4 and *5), only the latter two were detected among the subjects, occurring at an overall frequency of 3.99% and 2.17% respectively. The most common genotype was CYP2D6* 1/*10 (36.23%)followed by *1/*1 (30.43%) and *10/*10 (14.49%). None of the genotypes predicted poor metabolism. There was 26.81 % of the subjects with genotypes that predicted intermediate metabolism (lMs) and 2.90% ultra-rapid (URs) metabolism with the rests making up the extensive metabolisers (EMs). There was significant difference in the side effect profiles of the various genotype groups with the slower metabolisers (lMs) suffering more dizziness, headache, nausea, sweating and dry mouth with tramadol compared with the EMs and UMs. The slower metabolisers also had higher serum tramadol levels compared to the EMs and UMs at 8, 16 and 24 h. Four population pharmacokinetic models were developed: Model A (kel, Yol, kcp & kpc), ModelB (CLT, Yol), Model C (CLT, YS1) and Model D CCLTS1, Yol). There was a correlation between total clearance values (CL T) and the genotype groups (r= 0.5503, p<O.05). Generally, the mean total clearance predicted by the models from NPEM2 was lower (19.66 L/h) and the half-life longer (5.99 h) compared to the general values of 28 L/h and 5.2h respectively reported among the Western populations. This might be due to the differences in the CYP2D6 genotype with higher frequency of the CYP2D6* 10 allele among our Asian subjects that contributes to the 1M phenotype. In general, the UMs and EMs had 2.65 and 1.30 times faster total clearances compared to the IMs respectively. Mean total clearance values were 15.89, 18.23,23.24 and 42.15 L/h while mean half-liveswere 7.10, 6.78, 5.56 and 3.78 h among the IMs, EM1, EM2 and UMs respectively. Overall, NPEM2 perceived more diversity in the population than was IT2B. Tramadol's pharmacokinetics is influenced by CYP2D6 polymorphism whereby those having genotypes that predicted lower enzyme activity had slower clearance rates. Due to the heterogeneity of CYP2D6 polymorphism, our data was not sufficiently strong to be used to develop pharmacogenetic-based regimens. Therefore, further studies are suggested by including larger samples, more diverse genotypes and by examining another enzyme system (CYP3A4) with respect to tramadol's pharmacokinetics using population pharmacokinetic approaches. |
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| Physical Description: | xxxi, 418 leaves: ill.; 30 cm. |
| Bibliography: | Includes bibliographical references |