Effect of high-dose metronidazole on pharmacokinetics of oral budesonide and vice versa: a double drug interaction study.
Recent case reports suggest that addition of high-dose metronidazole might be associated with elevated plasma concentrations of substrates of cytochrome P450 (CYP) 3A. Because patients with fistulizing Crohn's disease benefit by using high doses of metronidazole for prolonged periods, this study's primary aim was to evaluate the effect of high-dose metronidazole on the pharmacokinetics of oral budesonide, a sensitive substrate of CYP3A commonly prescribed in acute inflammatory bowel disease. Twelve healthy adults received 1.5 g metronidazole per day over 1 week. The CYP3A-dependent metabolic profile of an oral dose of budesonide (3 mg) and that of endogenous cortisol were compared intraindividually before and after administration of metronidazole. There was neither a significant effect of high-dose metronidazole on the area under the plasma concentration-time curve (AUC) of budesonide (90% confidence interval, 79%-115%) nor on the AUC ratios of 6beta-hydroxybudesonide/budesonide and 16alpha-hydroxyprednisolone/budesonide. In parallel, metronidazole did not significantly alter formation of 6beta-hydroxycortisol. Vice versa, budesonide did not affect the AUC of metronidazole (90% confidence interval, 91%-100%). The authors conclude that in contrast to concomitant intake of other imidazoles such as ketoconazole, concomitant intake of metronidazole may not lead to serious safety concerns due to elevated systemic concentrations of the glucocorticoid budesonide.
Dilger
Karin
K
Department of Clinical Pharmacology, Institute of Pharmacology and Toxicology, University Hospital Tübingen, Otfried-Müller-Str. 45, D-72076 Tübingen, Germany.
Fux
Richard
R
Röck
Daniel
D
Mörike
Klaus
K
Gleiter
Christoph H
CH
D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D019540:Area Under Curve; D019819:Budesonide / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A / Q000097:blood / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D008795:Metronidazole / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry
D000900:Anti-Bacterial Agents; D000981:Antiprotozoal Agents; D008795:Metronidazole; D019819:Budesonide; C001380:6 beta-hydroxycortisol; D051544:Cytochrome P-450 CYP3A; D006854:Hydrocortisone