Foster D J, Somogyi A A, Dyer K R, White J M, Bochner F
Department of Cinical and Experimental Pharmacology, University of Adelaide, Adelaide, 5005, Australia.
Br J Clin Pharmacol. 2000 Nov;50(5):427-40. doi: 10.1046/j.1365-2125.2000.00272.x.
To investigate the steady-state pharmacokinetics of (R)- and (S)-methadone in a methadone maintenance population.
Eighteen patients recruited from a public methadone maintenance program underwent an interdosing interval pharmacokinetic study. Plasma and urine samples were collected and analysed for methadone and its major metabolite (EDDP) using stereoselective h.p.l.c. Methadone plasma protein binding was examined using ultrafiltration, and plasma alpha1-acid glycoprotein concentrations were quantified by radial immunoassay.
(R)-methadone had a significantly (P < 0.05) greater unbound fraction (mean 173%) and total renal clearance (182%) compared with (S)-methadone, while maximum measured plasma concentrations (83%) and apparent partial clearance of methadone to EDDP (76%) were significantly (P < 0.001) lower. When protein binding was considered (R)-methadone plasma clearance of the unbound fraction (59%) and apparent partial intrinsic clearance to EDDP (44%) were significantly (P < 0.01) lower than for (S)-methadone, while AUCtau_¿u¿ss (167%) was significantly (P < 0. 001) greater. There were no significant (P > 0.2) differences between the methadone enantiomers for AUCtauss, steady-state plasma clearance, trough plasma concentrations and unbound renal clearance. Patients excreted significantly (P < 0.0001) more (R)-methadone and (S)-EDDP than the corresponding enantiomers. Considerable interindividual variability was observed for the pharmacokinetic parameters, with coefficients of variation of up to 70%.
Steady-state pharmacokinetics of unbound methadone are stereoselective, and there is large interindividual variability consistent with CYP3A4 mediated metabolism to the major metabolite EDDP; the variability did not obscure a significant dose-plasma concentration relationship. Stereoselective differences in the pharmacokinetics of methadone may have important implications for pharmacokinetic-pharmacodynamic modelling but is unlikely to be important for therapeutic drug monitoring of methadone, in the setting of opioid dependence.
研究美沙酮维持治疗人群中（R）-和（S）-美沙酮的稳态药代动力学。
从一个公共美沙酮维持治疗项目招募了18名患者，进行给药间隔期药代动力学研究。采集血浆和尿液样本，采用立体选择性高效液相色谱法分析美沙酮及其主要代谢物（EDDP）。使用超滤法检测美沙酮血浆蛋白结合情况，通过放射免疫测定法定量血浆α1-酸性糖蛋白浓度。
与（S）-美沙酮相比，（R）-美沙酮的游离分数（平均173%）和总肾清除率（182%）显著更高（P<0.05），而最大实测血浆浓度（83%）和美沙酮向EDDP的表观部分清除率（76%）显著更低（P<0.001）。考虑蛋白结合时，（R）-美沙酮游离部分的血浆清除率（59%）和向EDDP的表观部分内在清除率（44%）显著低于（S）-美沙酮（P<0.01），而AUCtau_¿u¿ss（167%）显著更高（P<0.001）。美沙酮对映体在AUCtauss、稳态血浆清除率、谷浓度和游离肾清除率方面无显著差异（P>0.2）。患者排泄的（R）-美沙酮和（S）-EDDP显著多于相应对映体（P<0.0001）。药代动力学参数存在显著个体间差异，变异系数高达70%。
游离美沙酮的稳态药代动力学具有立体选择性，且个体间差异大，这与细胞色素P450 3A4介导的代谢为主要代谢物EDDP一致；这种差异并未掩盖显著的剂量-血浆浓度关系。美沙酮药代动力学的立体选择性差异可能对药代动力学-药效学建模具有重要意义，但在阿片类药物依赖的情况下，对美沙酮治疗药物监测可能不太重要。
