Mechanism-based inhibition of human cytochrome P4503A4 by domperidone

1. Domperidone was evaluated in direct and time-dependent cytochrome P450 (CYP) 3A inhibition assays in human liver microsomes with midazolam and testosterone as probe substrates. 2. Domperidone was found to be a modest mechanism-based inhibitor of human and rat CYP3A. For human CYP3A, the inactivation constant (K-i) is 12 mu M, and the maximum inactivation rate (k(inact)) is 0.037 min(-1). 3. A rat interaction study was conducted between midazolam and either a single dose or five daily doses of domperidone. Although a single oral dose of 10 mg kg(-1) domperidone did not affect the pharmacokinetics of 10 mg kg(-1) oral midazolam, five daily oral doses of domperidone almost doubled the area under the plasma concentration versus time curve (AUC) of midazolam, and increased the maximum plasma concentration (C-max) of midazolam by 72%. 4. Based on the simulation and rat in vitro-in vivo extrapolation, it is predicted that co-administration of domperidone in humans could modestly increase (approximately 50%) the exposure of drugs that are primarily cleared by CYP3A.