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- Title
Effects of metronidazole on midazolam metabolism in vitro and in vivo.
- Authors
Wang, J.-S.; Backman, J. T.; Kivistö, K. T.; Neuvonen, P. J.
- Abstract
Objective: Case reports have described elevated concentrations of CYP3A4 substrates (e.g. cyclosporin) during metronidazole treatment. Therefore, we wanted to study whether metronidazole affects CYP3A4 activity, using midazolam as a model substrate in vitro and in vivo. Methods: In the in vitro part of the study, the effects of various concentrations of metronidazole (0–500 µM) on the formation of 1'-hydroxymidazolam from midazolam were studied using human liver microsomal preparations (n=4). In the in vivo part, the effects of metronidazole on the pharmacokinetics and pharmacodynamics of oral midazolam were evaluated in a randomised, placebo-controlled cross-over study in ten healthy subjects. The subjects took either 400 mg metronidazole or matched placebo orally twice daily for 3 days. On day 3, 15 mg midazolam was administered orally. Plasma concentrations of midazolam and 1'-hydroxymidazolam were determined up to 24 h. The effects of midazolam were measured up to 10 h. Results: Metronidazole (10–500 µM) showed no inhibitory effect on 1'-hydroxymidazolam formation by human liver microsomes. In healthy volunteers, metronidazole had no statistically significant effects on the pharmacokinetics of midazolam and 1'-hydroxymidazolam, and also the ratio of 1'-hydroxymidazolam to midazolam in plasma remained unchanged by metronidazole. The four employed psychomotor tests did not show significant differences between the metronidazole and placebo phases. Conclusion: Metronidazole had no effects on the 1'-hydroxylation of midazolam in vitro or on the pharmacokinetics and pharmacodynamics of midazolam in vivo. These findings indicate that metronidazole is not an inhibitor of CYP3A4.
- Subjects
ANESTHETICS; PHARMACOKINETICS; PHARMACOLOGY; CELLS; PHARMACODYNAMICS
- Publication
European Journal of Clinical Pharmacology, 2000, Vol 56, Issue 8, p555
- ISSN
0031-6970
- Publication type
Article
- DOI
10.1007/s002280000201