Pharmacokinetics and first-pass elimination of metoprolol in rats: contribution of intestinal first-pass extraction to low bioavailability of metoprolol.
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.
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
In-Soo
IS
Yoon
Min-Koo
MK
Choi
Jung Sun
JS
Kim
Chang-Koo
CK
Shim
Suk-Jae
SJ
Chung
Dae-Duk
DD
Kim
D058671:Adrenergic beta-1 Receptor Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D001682:Biological Availability; D007275:Injections, Intravenous; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D058671:Adrenergic beta-1 Receptor Antagonists; D008790:Metoprolol