caa a22 4500 475818741 CHVBK 20180406123816.0 cr unu---uuuuu 170329e20001101xx s 000 0 eng 10.1007/s002280000201 doi (NATIONALLICENCE)springer-10.1007/s002280000201 Effects of metronidazole on midazolam metabolism in vitro and in vivo [Elektronische Daten] [J.-S. Wang, J.T. Backman, K.T. Kivistö, P.J. Neuvonen] 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 (0-500µM) 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 400mg metronidazole or matched placebo orally twice daily for 3days. On day 3, 15mg midazolam was administered orally. Plasma concentrations of midazolam and 1'-hydroxymidazolam were determined up to 24h. The effects of midazolam were measured up to 10h. Results: Metronidazole (10-500µM) 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. Springer-Verlag, 2000 Metronidazole Midazolam Cytochrome P450 3A4 nationallicence Wang J.-S Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland aut Backman J.T. Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland aut Kivistö K.T. Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland aut Neuvonen P.J. Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland aut European Journal of Clinical Pharmacology Springer-Verlag 56/8(2000-11-01), 555-559 0031-6970 56:8<555 2000 56 228 https://doi.org/10.1007/s002280000201 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s002280000201 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Wang J.-S Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland aut NATIONALLICENCE 700 1- Backman J.T. Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland aut NATIONALLICENCE 700 1- Kivistö K.T. Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland aut NATIONALLICENCE 700 1- Neuvonen P.J. Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland aut NATIONALLICENCE 773 0- European Journal of Clinical Pharmacology Springer-Verlag 56/8(2000-11-01), 555-559 0031-6970 56:8<555 2000 56 228 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer