Inhibition of the active principle of the weak opioid tilidine by the triazole antifungal voriconazole.

British Journal of Clinical Pharmacology
Barbara GrünGerd Mikus

Abstract

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 h*ng ml(-1), 95% confidence interval (CI) 1076.8, 1424.9 vs. 61 h*ng 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 voriconazol...Continue Reading

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