Mechanism-based inhibition of human cytochrome P4503A4 by domperidone.

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. 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 microM, and the maximum inactivation rate (k(inact)) is 0.037 min(-1). 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%. 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.