Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg, Germany.
Br J Clin Pharmacol. 2009 Nov;68(5):712-20. doi: 10.1111/j.1365-2125.2009.03498.x.
To investigate in vivo the influence of the potent CYP2C19 and CYP3A4 inhibitor voriconazole on the pharmacokinetics and analgesic effects of tilidine.
Sixteen healthy volunteers received voriconazole (400 mg) or placebo together with a single oral dose of tilidine (100 mg). Blood samples and urine were collected for 24 h and experimental pain was determined by using the cold pressor test. Noncompartimental analysis was performed to determine pharmacokinetic parameters of tilidine, nortilidine and voriconazole, whereas pharmacodynamic parameters were analysed by nonparametric repeated measures ANOVA (Friedman).
Voriconazole caused a 20-fold increase in exposition of tilidine in serum [AUC 1250.8 hng ml(-1), 95% confidence interval (CI) 1076.8, 1424.9 vs. 61 hng ml(-1), 95% CI 42.6, 80.9; P < 0.0001], whereas the AUC of nortilidine also increased 2.5-fold. After voriconazole much lower serum concentrations of bisnortilidine were observed. The onset of analgesic activity occurred later with voriconazole, which is in agreement with the prolonged t(max) of nortilidine (0.78 h, 95% CI 0.63, 0.93 vs. 2.5 h, 95% CI 1.85, 3.18; P < 0.0001) due to the additional inhibition of nortilidine metabolism to bisnortilidine. After voriconazole the AUC under the pain withdrawal-time curve was reduced compared with placebo (149 s h(-1), 95% CI 112, 185 vs. 175 s h(-1), 95% CI 138, 213; P < 0.016), mainly due to the shorter withdrawal time 0.75 h after tilidine administration.
Voriconazole significantly inhibited the sequential metabolism of tilidine with increased exposure of the active nortilidine. Furthermore, the incidence of adverse events was almost doubled after voriconazole and tilidine.
研究强效 CYP2C19 和 CYP3A4 抑制剂伏立康唑对替利定药代动力学和镇痛作用的体内影响。
16 名健康志愿者同时给予伏立康唑（400mg）或安慰剂和单剂量口服替利定（100mg）。采集 24 小时的血样和尿液，并通过冷压测试确定实验性疼痛。采用非房室分析方法测定替利定、去甲替利定和伏立康唑的药代动力学参数，而药效动力学参数则采用非参数重复测量方差分析（Friedman）进行分析。
伏立康唑使替利定在血清中的暴露量增加了 20 倍[AUC1250.8hngml-1，95%置信区间（CI）1076.8，1424.9 与 61hngml-1，95%CI42.6，80.9；P<0.0001]，而去甲替利定的 AUC 也增加了 2.5 倍。给予伏立康唑后，血清中双去甲替利定的浓度明显降低。与安慰剂相比，镇痛作用的出现时间较晚，这与去甲替利定的 t(max)延长（0.78h，95%CI0.63，0.93 与 2.5h，95%CI1.85，3.18；P<0.0001）一致，这是由于双去甲替利定代谢为去甲替利定的额外抑制作用。给予伏立康唑后，与安慰剂相比，疼痛撤药时间下的 AUC 减少（149s h-1，95%CI112，185 与 175s h-1，95%CI138，213；P<0.016），主要是由于替利定给药后撤药时间缩短至 0.75h。
伏立康唑显著抑制了替利定的序贯代谢，使活性去甲替利定的暴露量增加。此外，给予伏立康唑和替利定后，不良事件的发生率几乎增加了一倍。
