Pharmacokinetics of the Monocarboxylate Transporter 1 Inhibitor AZD3965 in Mice: Potential Enterohepatic Circulation and Target-Mediated Disposition.

Abstract

To evaluate the pharmacokinetics (PK) of the monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 in mice after IV and oral administration and to develop mechanistic PK models to assess the potential enterohepatic circulation (EHC) and target-mediated drugdisposition (TMDD) of AZD3965. Female BALB/c mice were administered AZD3965 by IV injection (10, 50 and 100mg/kg) or oral gavage (100mg/kg). Plasma samples were analyzed using LC/MS/MS, and PK parameters determined by compartmental and non-compartmental analyses. AZD3965 exhibited a large volume of distribution and rapid oral absorption, with a high oral bioavailability. Prominent reentry peaks were observed after both oral and IV administration, suggesting potential EHC of AZD3965 or of a potential glucuronide conjugate. The dose-dependent studies indicated greater than proportional increases in exposure, an increase in the terminal half-life, and decrease in clearance and volume of distribution with increasing IV doses, indicating nonlinear pharmacokinetics and potential TMDD of AZD3965. Mechanistic compartmental models were developed to characterize the complex pharmacokinetics of AZD3965. The current study represents the first comprehensive report of the pharmacokinetics of AZD3965 in mice, indicating the potential contribution of EHC and TMDD in the disposition of AZD3965.