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

Abstract

1. 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.

2. 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 (E_G and E_H, 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.

3. The E_G in rats was predicted from in vitro clearance and/or permeability data utilizing the Q_Gut model and well-stirred model (0.347 and 0.626, respectively). The predicted E_G values were in good agreement with the observed in vivo E_G (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.

Keywords::

• Metoprolol
• pharmacokinetics
• intestinal and hepatic first-pass extraction
• rats

Acknowledgement

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST) (2009-0083533).

Declaration of interest

The authors report no conflict of interest.