Pawlowska M, Bogiel M, Duda J, Sieradzki E
Institute of Biotechnology and Antibiotics, Warsaw, Poland.
Faculty of Pharmacy, Department of Applied Pharmacy and Bioengineering, Medical University of Warsaw, Warsaw, Poland.
Eur J Clin Pharmacol. 2015 Jun;71(6):699-705. doi: 10.1007/s00228-015-1856-5. Epub 2015 May 9.
This is the first study that connects pharmacokinetics of tolperisone with genetic polymorphism of the enzymes involved in its metabolism in human. We aimed to identify the influence of polymorphism of two main enzymes (CYP2D6 and CYP2C19) on pharmacokinetic profile of parent drug.
In a single-dose study, 28 healthy Caucasian male volunteers received an oral dose of 150 mg of tolperisone. The subjects were genotyped with respect to CYP2D6 and CYP2C19 enzymes. Plasma was sampled for up to 12 h post dose, followed by quantification of tolperisone by a fully validated HPLC-tandem mass spectrometry (MS/MS) method. The pharmacokinetic parameters were estimated using a non-compartmental method and compared statistically at level p < 0.05 across the genotyped groups.
High variability (exceeded 100%) of main bioavailability parameters (AUCt, AUC(inf), C(max)) was observed in the whole group of subjects. An essential difference in the pharmacokinetics of tolperisone of quick metabolizers whose genotype expressed wild homozygote CYP2D6 *1/*1 with respect to heterozygous *1/*4 and *1/*5 subjects was demonstrated. The mean AUC(inf) was 2.1- and 3.4-fold higher in *1/*4 and *1/*5, respectively, than in *1/*1 subjects. In case of Cmax, the differences were greater and reached maximally 3.8 times (mean values 54.00, 98.85, and 205.20 ng/mL for CYP2D6 *1/*1, *1/*4, and *1/*5, respectively). Values of the parameters for the one subject that expressed *4/*4 genotype were even 8.5 times higher than in subjects with extensive or intermediate phenotype. Although CYP2C19 *1/*2 subjects had higher AUCt, AUC(inf), and Cmax values than *1/*1, no statistically significant differences were observed. Oral clearance (CL/F) significantly decreased by 65.7% in heterozygous *1/*2 relative to homozygous *1/*1 extensive metabolizers.
In this study, we first demonstrated the effect of CYP2D6 polymorphism on pharmacokinetics of tolperisone in Caucasian subjects. The contribution of CYP2C19 enzyme seems to be less important.
本研究首次将托哌酮的药代动力学与人体中参与其代谢的酶的基因多态性联系起来。我们旨在确定两种主要酶（CYP2D6和CYP2C19）的多态性对母体药物药代动力学特征的影响。
在一项单剂量研究中，28名健康的白种男性志愿者口服150毫克托哌酮。对受试者进行CYP2D6和CYP2C19酶的基因分型。给药后长达12小时采集血浆样本，然后通过完全验证的高效液相色谱-串联质谱（MS/MS）方法对托哌酮进行定量。使用非房室方法估计药代动力学参数，并在基因分型组间进行p<0.05水平的统计学比较。
在整个受试者组中观察到主要生物利用度参数（AUCt、AUC(inf)、Cmax）的高变异性（超过100%）。对于快速代谢者，其基因型表现为野生纯合子CYP2D6 *1/1，与杂合子1/4和1/*5受试者相比，托哌酮的药代动力学存在本质差异。*1/4和1/5受试者的平均AUC(inf)分别比1/*1受试者高2.1倍和3.4倍。在Cmax方面，差异更大，最大达到3.8倍（CYP2D6 *1/*1、*1/4和1/5受试者的平均值分别为54.00、98.85和205.20 ng/mL）。一名表现为4/*4基因型受试者的参数值甚至比具有广泛或中间表型的受试者高8.5倍。虽然CYP2C19 *1/2受试者的AUCt、AUC(inf)和Cmax值高于1/1，但未观察到统计学上的显著差异。相对于纯合子1/1广泛代谢者，杂合子1/*2的口服清除率（CL/F）显著降低了65.7%。
在本研究中，我们首次证明了CYP2D6多态性对高加索受试者中托哌酮药代动力学的影响。CYP2C19酶的贡献似乎不太重要。
