The intestine is the major site of interaction between midazolam and verapamil

Abstract

Objective To determine the site of the drug interaction between verapamil and midazolam, we examined the effect of verapamil on intestinal and hepatic CYP3A activity in vivo using midazolam as a CYP3A substrate. Methods Five healthy subjects (ages 23-48 yrs and BMI ranging 21.9–30.4) were enrolled and completed the study. Midazolam was given intravenously (0.05 mg/kg over 30 min) and orally (4 mg) on consecutive days and serial blood samples were obtained. The intravenous and oral midazolam studies were repeated after a seven-day regimen of verapamil (sustained release formula, 240 mg, once daily in the morning). Blood midazolam concentrations were determined by LC/MS. Results The oral clearance of midazolam was decreased 4-fold (157.76 ± 135.89 L/hr to 39.87 ± 15.07 L/hr, p = 0.16) and the systemic clearance was also decreased (34.65 ± 14.18 L/hr to 21.35 ± 5.92 L/hr, p = 0.10) after verapamil treatment. The oral bioavailability (0.33 ± 0.14 to 0.59 ± 0.17, p = 0.02) and intestinal availability (0.49 ± 0.16 to 0.73 ± 0.22, p = 0.04) were significantly increased. However, verapamil did not significantly (p = 0.11) alter the hepatic extraction ratio (0.36 ± 0.19 to 0.21 ± 0.03) of midazolam. Conclusion These data indicate that the intestine is the major site of the interaction between midazolam and verapamil. Clinical Pharmacology & Therapeutics (2004) 75, P86–P86; doi: 10.1016/j.clpt.2003.11.329