Purpose: BMS-387032, a novel cyclin-dependent kinase 2 inhibitor, is currently in phase I clinical trials for anticancer therapy. The oral bioavailability of BMS-387032 has been found to be about 31% in rats. Absorption and first-pass metabolism were evaluated as possible reasons for the incomplete oral bioavailability in rats.
Methods: Male Sprague-Dawley rats were given single doses of BMS-387032 intraarterially (9.1 mg/kg), orally (9.1 mg/kg), or intraportally (10 mg/kg). The routes of excretion of BMS-387032 after intravenous dosing were investigated in bile-duct-cannulated rats. The rate of metabolism of BMS-387032 was investigated in liver microsomes. The permeability of BMS-387032 was evaluated using Caco-2 cells, an in vitro model of the intestinal epithelium. To determine if BMS-387032 was a P-glycoprotein substrate, brain uptake studies were conducted in P-glycoprotein knockout versus wildtype mice.
Results: The exposure in rats after an intraportal dose was similar to that after an intraarterial dose, indicating that absorption may play a greater role than liver first-pass metabolism in the low oral bioavailability seen in rats. After an intravenous dose, the percent of dose excreted unchanged in the urine and bile over a 9-h period was 28% and 11%, respectively. In vitro studies in rat liver microsomes showed low rates of metabolism of BMS-387032. The Caco-2 cell permeability of BMS-387032 was <15 nm/s in the apical to basolateral direction, and 161 nm/s in the basolateral to apical direction, indicating that it may be a substrate for an intestinal efflux transporter. A P-glycoprotein binding assay showed that BMS-387032 might be a P-glycoprotein modulator. Brain penetration studies in mice showed brain levels of BMS-387032 about 3.5-fold higher in P-glycoprotein knockout mice than in wildtype mice, providing evidence of BMS-387032 being a P-glycoprotein substrate.
Conclusions: Poor absorption may be playing a greater role than extensive first-pass metabolism in the incomplete oral bioavailability of BMS-387032 seen in rats. The efflux transporter, P-glycoprotein, may be responsible for limiting absorption, as BMS-387032 appears to be a substrate of P-glycoprotein.