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


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.
Grün
Barbara
B
Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg, Germany.
Krautter
Stefanie
S
Riedel
Klaus-Dieter
KD
Mikus
Gerd
G
D000328:Adult; D000701:Analgesics, Opioid / Q000493:pharmacokinetics*; D000704:Analysis of Variance; D000935:Antifungal Agents / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines / Q000493:pharmacokinetics*; D013993:Tilidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D014230:Triazoles / Q000493:pharmacokinetics*; D065819:Voriconazole; D055815:Young Adult
D000701:Analgesics, Opioid; D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; C062490:nortilidine; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D013993:Tilidine; D065819:Voriconazole