Department of Pharmacology, Clinical Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Köln, Germany.
Drug Metab Dispos. 2011 May;39(5):927-32. doi: 10.1124/dmd.110.036921. Epub 2011 Jan 26.
The pharmacokinetics of repaglinide shows pronounced interindividual variability, for which several reasons have been considered, including interactions with drugs inhibiting CYP2C8 and CYP2C8 genetic polymorphism. However, existing data on the role of genetic polymorphisms in repaglinide disposition are not fully consistent. We studied the effect of CYP2C83 on the pharmacokinetics and pharmacodynamics of repaglinide in 29 healthy whites carrying CYP2C83/3 (n = 4), CYP2C81/3 (n = 13), or CYP2C81/1 (n = 12). After administration of a single dose of 2 mg of repaglinide, blood was drawn for assessment of repaglinide pharmacokinetics and pharmacodynamics, and urine was collected to quantify the main repaglinide metabolites M1 and M4 up to 24 h postdose. Repaglinide and the metabolites were quantified by liquid chromatography-tandem mass spectrometry. Considering only the effect of CYP2C83, the mean (95% confidence interval) area under the time-concentration curve (AUC) from zero to infinity of repaglinide was 72.4 (6.7-138.0), 97.2 (59.2-135.2), and 105.9 (52.4-159.3) ng · ml(-1) · h and the maximal concentration (C(max)) was 38.5 (3.8-73.2), 50.3 (37.5-63.0), and 60.3 (31.5-89.1) ng · ml(-1), respectively, in carriers of CYP2C8*3/3, CYP2C81/3, and CYP2C81/1 [p > 0.05, one-way analysis of variance (ANOVA)]. In addition, for urinary metabolite excretion and pharmacodynamic parameters, i.e., mean and maximal changes in insulin and glucose concentration, no significant differences between CYP2C8 genotypes were observed. Likewise, no significant effects on the pharmacokinetics or pharmacodynamics were observed when AUC and C(max) of repaglinide were corrected for reported effects of the SLCO1B1 521T>C polymorphism or when both polymorphisms were tested in a two-way ANOVA. In conclusion, CYP2C83 does not seem to play an important role in the pharmacokinetics and pharmacodynamics of repaglinide given in a therapeutic dose.
瑞格列奈的药代动力学表现出明显的个体间差异，其原因有多种，包括与抑制 CYP2C8 和 CYP2C8 遗传多态性的药物相互作用。然而，关于遗传多态性在瑞格列奈处置中的作用的现有数据并不完全一致。我们研究了 CYP2C83 对 29 名携带 CYP2C83/3（n=4）、CYP2C81/3（n=13）或 CYP2C81/1（n=12）的健康白种人的瑞格列奈药代动力学和药效学的影响。给予单剂量 2 毫克瑞格列奈后，抽取血液评估瑞格列奈的药代动力学和药效学，并收集尿液，在给药后 24 小时内定量测定主要瑞格列奈代谢物 M1 和 M4。通过液相色谱-串联质谱法定量测定瑞格列奈和代谢物。仅考虑 CYP2C83 的影响，瑞格列奈的药代动力学和药效学参数 AUC（0-∞）的平均值（95%置信区间）分别为 72.4（6.7-138.0）、97.2（59.2-135.2）和 105.9（52.4-159.3）ng·ml-1·h，Cmax 分别为 38.5（3.8-73.2）、50.3（37.5-63.0）和 60.3（31.5-89.1）ng·ml-1，在 CYP2C8*3/3、CYP2C81/3 和 CYP2C81/1 携带者中分别为 38.5（3.8-73.2）、50.3（37.5-63.0）和 60.3（31.5-89.1）ng·ml-1（p＞0.05，单因素方差分析（ANOVA））。此外，对于尿代谢物排泄和药效学参数，即胰岛素和葡萄糖浓度的平均和最大变化，在 CYP2C8 基因型之间未观察到显著差异。同样，当 AUC 和 Cmax 的瑞格列奈校正报告的 SLCO1B1 521T>C 多态性的影响时，或当两种多态性在双向 ANOVA 中进行测试时，未观察到对药代动力学或药效学的显著影响。总之，在治疗剂量下，CYP2C83 似乎在瑞格列奈的药代动力学和药效学中不起重要作用。
