Influence of rifampicin pretreatment on the pharmacokinetics of tinidazolein healthy male volunteers

Objective: To investigate the effect of pretreatment with rifampicin (rifam pin) on the pharmacokinetics of tinidazole in healthy male volunteers. Design: Before/after non-blinded investigation conducted in healthy volunte ers. Study Participants: 12 healthy male volunteers with a mean age of 24 +/- 3 years. Methods: After an overnight fast, tinidazole (500mg tablet) was administere d to the volunteers, either alone or after a 5-day pretreatment period with a once-daily dose of rifampicin 600mg (2 x 300mg capsules) under direct ob servation. Serum concentrations of tinidazole were measured by reverse-phas e high performance liquid chromatography. Pharmacokinetic parameters were d etermined from noncompartmental model analysis using the computer program R AMKIN. Results: A significant difference was observed in area under the concentrat ion-time curve (AUC) from 0 to 48 hours (254.77 +/- 31.46 vs 208.07 +/- 25. 57 mg .h/L, p < 0.0001), AUC from 0 to infinity (299.86 +/- 47.70 vs 231.54 +/- 36.19 mg<bullet>h/L, p < 0.0001], elimination half-life (16.98 +/- 2.7 3 vs 13.93 +/- 3.45h, p < 0.0018) and clearance (27.62 +/- 3.61 vs 35.82 +/ - 4.95 ml/h/kg, p < 0.000 1) of tinidazole administered before and after ri fampicin pretreatment. However, peak concentration (C-max), time to reach C -max and apparent volume of distribution were not affected significantly. Conclusions: Rifampicin pretreatment reduced the AUC of tinidazole by 23% a nd increased the clearance by 29%. This may be due to increased metabolism of tinidazole as a result of the induction of cytochrome P450 2C9 and 3A4 i n liver/intestine and/or P-glycoprotein-mediated exsorption into the intest ines. This interaction, however, may not have significant clinical relevanc e and does not warrant dosage adjustment because the extent of alteration i n bioavailability of tinidazole is less than 25%.