Effects of oral clotrimazole troches on the pharmacokinetics of oral and intravenous midazolam

Autor: Stacy S. Shord, Robert E. Molokie, Joseph R. Camp, Charles L. Baum, Hyunyoung Jeong, Eva M. Vasquez, Hui Xie, Lingtak Neander Chan
Rok vydání: 2010
Předmět:
Zdroj: British Journal of Clinical Pharmacology. 69:160-166
ISSN: 1365-2125
0306-5251
DOI: 10.1111/j.1365-2125.2009.03559.x
Popis: WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Clotrimazole troches are commonly used as prophylaxis for thrush that may develop in immunocompromised patients. • Conflicting data suggest that clotrimazole may induce or inhibit cytochrome P450 (CYP) 3A4. WHAT THIS STUDY ADDS? • We have demonstrated that clotrimazole increased the area under the concentration–time curve and decreased the apparent oral clearance of midazolam following oral administration without affecting the pharmacokinetic properties of midazolam after intravenous administration. • These data permit the suggestion that clotrimazole may cause clinically relevant changes in the pharmacokinetics or pharmacodynamics of concurrently administered oral CYP3A substrates that undergo significant first-pass metabolism in this patient population. AIMS The aim of the study was to determine the effects of oral clotrimazole troches on the pharmacokinetics of oral and intravenous midazolam in the plasma. METHODS We conducted a randomized, open-label, four-way crossover study in 10 healthy volunteers. Each volunteer received oral midazolam 2 mg or intravenous midazolam 0.025 mg kg−1 with and without oral clotrimazole troches 10 mg taken three times daily for 5 days. Each study period was separated by 14 days. Serial blood samples were collected up to 24 h after oral midazolam and 6 h after intravenous midazolam. Plasma concentrations for midazolam and its metabolite 1-hydroxymidazolam were measured and fitted to a noncompartmental model to estimate the pharmacokinetic parameters. RESULTS Ten healthy volunteers aged 21–26 years provided written informed consent and were enrolled into the study. Clotrimazole decreased the apparent oral clearance of midazolam from 57 ± 13 l h−1[95% confidence interval 48, 66] to 36 ± 9.8 l h−1 (95% confidence interval 29, 43) (P= 0.003). These changes were accompanied by a decrease in the area under the concentration–time curve (mean difference 22 µg h−1 l−1, P= 0.001) and bioavailability (mean difference 0.21, P= NS). There were no significant differences in the systemic clearance of midazolam with or without clotrimazole troches. CONCLUSIONS Oral clotrimazole troches decreased the apparent oral clearance of midazolam; no significant differences in the systemic clearance of midazolam were found.
Databáze: OpenAIRE
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