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The Effect of Diltiazem and Nifedipine on the Rate of Metabolism of Midazolam

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Technical Report

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Uniformed Services University Of The Health Sciences Bethesda United States

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Midazolam is the preferred benzodiazepine in anesthesia during the perioperative period because of its amnestic and anxiolytic properties, and short duration of action. Several clinical trials have reported prolonged sedative effects when midazolam is administered with a calcium channel blocker such as diltiazem. The cause of the prolonged half-life of midazolam could be competitive inhibition of midazolam s metabolism at the level of the P450 CYP3A enzymes when concomitantly administered with calcium channel blockers. In this experimental, quantitative in vitro study we examined the rate of inhibition of the metabolism of midazolam when coincubated with the calcium channel blockers diltiazem and nifedipine using three human liver microsomes. The results of our in vitro study demonstrated that formation of alpha-hydroxymidazolam was inhibited by both nifedipine and ditiazem. Nifedipine was the most potent inhibitor with a Ki of 5.730.31uM. Diltiazem was one order- of- magnitude less potent with a Ki of 80.7or-28.7uM.Kinetic analysis showed a mixed type inhibition for both nifedipine and diltiazem.

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