Bidstrup Tanja Busk, Stilling Nicolaj, Damkier Per, Scharling Birgitte, Thomsen Mikael Søndergård, Brøsen Kim
Odense University Hospital and Clinical Pharmacology, University of Southern Denmark, Winsløwparken 192, 5000 Odense C, Denmark,
Eur J Clin Pharmacol. 2004 Apr;60(2):109-14. doi: 10.1007/s00228-004-0746-z. Epub 2004 Mar 19.
To investigate if rifampicin is both an inducer and an inhibitor of repaglinide metabolism, it was determined whether the timing of rifampicin co-administration influences the pharmacokinetics of repaglinide.
Male volunteers ( n=12) participated in a randomised, two-period, crossover trial evaluating the effect of multiple doses of 600 mg rifampicin once daily for 7 days on repaglinide metabolism. Subjects were, after baseline measurements of repaglinide pharmacokinetics, randomised to receive, on either day 7 or day 8 of the rifampicin administration period, a single dose of 4 mg repaglinide and vice versa in the following period.
When repaglinide was given, together with the last rifampicin dose, on day 7, an almost 50% reduction of the median repaglinide area under the plasma concentration-time curve (AUC) was observed. Neither the peak plasma concentration (C(max)), time to reach C(max) (t(max)) nor terminal half-life (t(1/2)) was statistically significantly affected. When repaglinide was given on day 8, 24 h after the last rifampicin dose, an almost 80% reduction of the median repaglinide AUC was observed. The median C(max) was now statistically significantly reduced from 35 ng/ml to 7.5 ng/ml. Neither t(max) nor t(1/2) was significantly affected.
When rifampicin and repaglinide are administered concomitantly, rifampicin seems to act as both an inducer and an inhibitor of the metabolism of repaglinide. After discontinuing rifampicin administration, while the inductive effect on CYP3A4 and probably also CYP2C8 is still present, an even more marked reduction in the plasma concentration of repaglinide was observed. Our results suggest that concomitant administration of rifampicin and repaglinide may cause a clinically relevant decrease in the glucose-lowering effect of repaglinide, in particular when rifampicin treatment is discontinued or if the drugs are not administered simultaneously or within a few hours of each other.
为研究利福平是否既是瑞格列奈代谢的诱导剂又是抑制剂，本研究确定了利福平联合给药的时间是否会影响瑞格列奈的药代动力学。
男性志愿者（n = 12）参与了一项随机、两周期、交叉试验，评估每日一次多剂量600 mg利福平连续7天对瑞格列奈代谢的影响。在对瑞格列奈药代动力学进行基线测量后，受试者被随机分为两组，在利福平给药期的第7天或第8天接受单次4 mg瑞格列奈给药，在下一周期则相反。
当在第7天与最后一剂利福平同时给予瑞格列奈时，观察到血浆浓度 - 时间曲线下瑞格列奈的中位面积（AUC）降低了近50%。血浆峰浓度（C(max)）、达到C(max)的时间（t(max)）以及末端半衰期（t(1/2)）均未受到统计学显著影响。当在最后一剂利福平给药24小时后的第8天给予瑞格列奈时，观察到瑞格列奈中位AUC降低了近80%。此时中位C(max)从35 ng/ml统计学显著降低至7.5 ng/ml。t(max)和t(1/2)均未受到显著影响。
当利福平和瑞格列奈同时给药时，利福平似乎既是瑞格列奈代谢的诱导剂又是抑制剂。在停止利福平给药后，虽然对CYP3A4以及可能对CYP2C8的诱导作用仍然存在，但观察到瑞格列奈的血浆浓度有更显著的降低。我们的结果表明，利福平和瑞格列奈同时给药可能会导致瑞格列奈的降糖效果出现具有临床意义的降低，特别是当利福平治疗停止时，或者如果两种药物没有同时给药或在彼此几小时内给药。
