人体内反式曲马朵及其活性代谢产物反式氧去甲基曲马朵对映体的药物动力学

摘要

AIM: To study the stereoselectivity in phannacokinetics of the enantiomers of trans-tramadol (trans-T) and its active metabolite, trans-O-demethyltramadol (Ml) in human subjects. METHODS: Trans-T hydrochloride sustained-release tablets were taken orally by 12 healthy male volunteers. After a multiple dosage schedule, the serum concentrations of (＋)-trans-T, (-)-trans-T, (＋)-Ml, and (-)-Ml were determined in serum by high performance capillary electrophoresis (HPCE).RESULTS: (＋)-Trans-T, (-)-trans-T, (＋)-Ml and (-)-Ml in human serum were separated by HPCE. The linear range was 2.5-320 μg/L for the enantiomers of trans-T, and 2.5-50 μg/L for the enantiomers of Ml. For the enantiomers of trans-T and Mi, the intraday and inter-day RSD were less than 15％ and 20％,and the relative recoveries were 94.3％-106.2％ and 90.4％-107.8％, respectively; the limit of quantitation was 1.25 μg/L. The serum concentrations of the enantiomers of trans-T reached a steady state in 12 subjects on d 4 after the initial administration. The steady state serum concentrations of (＋)-trans-T were higher than that of (-)-trans-T at every sampling points in the subjects. The differences were significant in the main pharmacokinetic parameters between (＋)-trans-T and (-)-trans-T except Tmax. The serum concentrations of(-)-Ml were higher than that of (＋)-Ml in most subjects and at most sampling time points. There were significant differences in Cmax and Cmin between the enantiomers of Ml. CONCLUSION: The pharmacokinetics of trans-T and Ml was found to be stereoselective. (＋)-Trans-T was shown to be absorbed completely, but eliminated more slowly. The phannacokinetic stereoselectivity of Ml was different among human subjects.%目的：研究反式曲马朵(trans-T)及其活性代谢产物反式氧去甲基曲马朵(Ml)的人体药代动力学立体选择性.方法：12名健康男性受试者口服多剂量盐酸trans-T缓释片后，采用高效毛细管电泳(HPCE)法测定血清中trans-T及M1对映体的浓度.结果：血清中trans-T对映体浓度达稳态后，不同时间血清中(＋)-trans-T的浓度均高于(-)-trans-T的浓度，两对映体除Tmax以外的药代动力学参数的差异均有显著性.在大多数受试者体内和大多数取血时间点，(-)-Ml的浓度高于(＋)-Ml的浓度；在不同受试者体内，血清中Ml对映体浓度的比值差别较大，两对映体的Cmax和Cmin差异有显著性.结论：trans-T和M1具有药代动力学立体选择性.人体对(＋)-trans-T比对(-)-trans-T吸收完全，消除慢；在不同受试者体内，Ml的药代动力学立体选择性是不同的.