PRESYSTEMIC AND SYSTEMIC INTESTINAL METABOLISM OF FENOTEROL IN THE CONSCIOUS RAT

  • 1 January 1985
    • journal article
    • research article
    • Vol. 13  (4) , 464-470
Abstract
The intestinal and liver first pass metabolism of fenoterol hydrobromide [.alpha..beta.-sympathomimetic] was investigated in the conscious rat. Fenoterol plasma concentrations (2-1000 ng/ml) were measured with a new HPLC [high-performance liquid chromatography] determination using electrochemical detection. After intraduodenal administration. Fenoterol was incompletely absorbed (47-66% not absorbed). Presystemic intestinal (EGpre) and liver (EH) extraction ratios, EGpre = 0.93 .+-. 0.01, EH = 0.67 .+-. 0.04, were calculated from AUC [area under the curve] value after intraduodenal, intraportal and i.v. administration. Saturation of intestinal and/or liver metabolism was checked by using 3 dose levela t different administration routes. Total systemic availability after intraduodenal administration ranged from 0.8 (10 mg/kg) to 1.2% (40 mg/kg). The contribution of the splanchnic region to the systemic clearance of fenoterol was assessed by measuring fenoterol and fenoterol-glucuronide concentrations in arterial and portal venous blood under steady state conditions. During i.v. infusion (30 .mu.g fenoterol/min per kg), an intestinal extraction ratio of EG = 0.26 was observed. After i.v. administration of fenoterol (1 and 2 mg/kg), dose-dependent pharmacokinetics were observed. Doubling of the dose resulted in an increase of systemic clearance (CI = 53.8 .+-. 2.7 and 74.4 .+-. 1.8 ml/min per kg) and distribution volume (Vss = 0.95 .+-. 0.13 and 1.21 .+-. 0.11 l/kg); the mean residence time (17.9 .+-. 2.4 and 16.3 .+-. 1.4 min) and terminal half-life (45.8 .+-. 5.5 and 46.8 .+-. 2.8 min) were not changed.