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.

Identification of a Potent, Selective, and Efficacious Phosphatidylinositol 3-Kinase δ (PI3Kδ) Inhibitor for the Treatment of Immunological Disorders.

PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4'-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.

Metabolism of alpha-phosphonosulfonate squalene synthase inhibitors. I. Disposition of a farnesylethyl alpha-phosphonosulfonate and ester prodrugs in rats.

The disposition of I [(E,E)-6,10,14-trimethyl-1-phosphono-5,9, 13-pentadecatriene-1-sulfonic acid] and its mono- (II), di- (III), and triester (IV) prodrugs in rats was studied with 14C-labeled compounds. After iv administration of I (15 micromol/kg), radioactivity in plasma was measurable up to 96 hr and averaged 0. 026 microg-eq/ml. I accounted for >50% of the radioactivity in plasma and had an apparent half-life of 4 hr. After oral administration of the same dose, the maximal plasma concentration of radioactivity averaged 0.108 microg-eq/ml at 6 hr. In 96 hr, 19 and 73% of the iv dose and 2 and 97% of the po dose was excreted in urine and feces, respectively. The absorption was 2.4%, based on the plasma data. In 12 hr after an iv dose of I to bile duct-cannulated rats, 41 and 14% of the dose was excreted in bile and urine, respectively. I accounted for 51% of the radioactivity in bile and a negligible amount in urine. At 12 hr after iv dosing, liver retained 31% of the dose. No accumulation of radioactivity in bone was observed. I (3%) and II (6%) were poorly absorbed. Enhanced absorption was observed for III (80%) and IV (45%). No I or metabolites of I were found in bile or urine of rats dosed with the prodrugs. The structures of two metabolites each for I, III, and IV were proposed. Together, they accounted for >80% of the radioactivity in urine and approximately 50% of the radioactivity in bile for each compound. Metabolism appeared to occur primarily at the farnesyl moiety, presumably by the same pathways as for farnesyl-1-pyrophosphate.