Effects of metronidazole on midazolam metabolism in vitro and in vivo.
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 microM) 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 microM) 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.


CONCLUSIONS
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.
Wang
J S
JS
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
Backman
J T
JT
Kivistö
K T
KT
Neuvonen
P J
PJ
D000284:Administration, Oral; D000328:Adult; D000890:Anti-Infective Agents / Q000494:pharmacology*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008795:Metronidazole / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008874:Midazolam / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects
D000890:Anti-Infective Agents; D006993:Hypnotics and Sedatives; D008795:Metronidazole; D003577:Cytochrome P-450 Enzyme System; C040081:1-hydroxymethylmidazolam; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam