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Keywords:

  • CYP2C19;
  • CYP3A4;
  • inhibition;
  • metabolism;
  • nortilidine;
  • tilidine

WHAT IS ALREADY KNOWN ABOUT THE SUBJECT

• Tilidine, a World Health Organization level II analgesic, is a high extraction drug subject to pronounced first-pass metabolism, resulting in a low absolute bioavailability.

• The analgesic activity of tilidine is almost exclusively exerted through its metabolite nortilidine, which easily penetrates the blood–brain barrier and binds to the µ-opioid receptor as a potent agonist.

• In vitro, tilidine has been shown to be metabolized to nortilidine by N-demethylation via CYP3A4 and CYP2C19; furthermore, strong CYP3A4 and CYP2C19 inhibitors inhibited the formation of nortilidine, suggesting that these inhibitors will lead to a reduction of tilidine efficiency in vivo.

WHAT THIS PAPER ADDS

• Co-administration of tilidine and the potent CYP3A4 and CYP2C19 inhibitor voriconazole resulted in a major pharmacokinetic interaction that was partly associated with changes in the analgesic effect.

• Voriconazole inhibits both metabolic steps in the sequential metabolism of tilidine resulting in an increased exposure of the active nortilidine.

• The incidence of adverse reactions was also significantly increased.

AIMS

To investigate in vivo the influence of the potent CYP2C19 and CYP3A4 inhibitor voriconazole on the pharmacokinetics and analgesic effects of tilidine.

METHODS

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).

RESULTS

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 tmax 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.

CONCLUSIONS

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.