Pharmacokinetics and first-pass elimination of metoprolol in rats: contribution of intestinal first-pass extraction to low bioavailability of metoprolol

Abstract

The pharmacokinetics of metoprolol after intravenous (IV) (0.5, 1, and 2 mg/kg) and oral (1, 2, and 5 mg/kg) administration, and the intestinal and hepatic first-pass extraction of metoprolol after IV, intraportal, and intraduodenal (1 and 2 mg/kg) administration were comprehensively assessed in rats.Metoprolol exhibited dose-independent pharmacokinetics after IV administration, and dose-dependent pharmacokinetics after oral administration probably due to the saturable first-pass extraction of metoprolol. At doses where metoprolol exhibited dose-independent pharmacokinetics (1 and 2 mg/kg), complete absorption (>99.2%) and low F (<0.245) after oral administration were observed. The intestinal and hepatic first-pass extraction ratio (EG and EH, respectively) of metoprolol were approximately 0.45 and 0.60, respectively (equivalent to approximately 45% and 30% of orally administered dose, respectively), suggesting considerable contribution of intestinal first-pass extraction to the low F of metoprolol in rats.The EG in rats was predicted from in vitro clearance and/or permeability data utilizing the QGut model and well-stirred model (0.347 and 0.626, respectively). The predicted EG values were in good agreement with the observed in vivo EG (0.492–0.443), suggesting the utility of the prediction of in vivo intestinal first-pass extraction from the in vitro clearance using intestinal microsomes.