Hepatic Extraction of Hexarelin, a New Peptidic GH Secretagogue, in the Isolated Perfused Rat Liver

Abstract

Purpose. To assess the hepatic extraction of hexarelin (HEX), a novel peptidyl GH secretagogue, in the isolated perfused rat model and document the in vitro binding of HEX to plasma proteins using plasma from rats, dogs, pigs, and humans.

Methods. Rat liver was perfused in situ using a recirculating system. The recirculating perfusate consisted of a Krebs Henseleit buffer containing 20% (v/v) prewashed bovine red blood cells, 1 % albumin, and 1g/L dextrose. Three HEX concentrations of 5, 50, and 500 ng/ml were examined. In vitro plasma binding was determined by the ultrafiltration method.

Results. The disappearance rate constant (K), half-life (t_1/2), clearance (Cl), and hepatic extraction ratio (E) were: K = 0.013−0.014 min⁻¹, t_1/2 = 45−55 min, Cl = 0.345−0.401 ml/min/g liver, and E = 19-21% for the different concentrations of HEX. A linear increase in AUC (270-24334 min pmol/ml) was observed with increasing concentrations. Binding of HEX to plasma proteins of rats, dogs, pigs, and humans was 68.7 ± 0.8%, 78.7 ± 0.6%, 67.3 ± 0.7%, and 65.2 ± 0.6% respectively. Plasma binding was concentration-independent in the range between 0.003−3 μM for the four species examined.

Conclusions. These results show that 1) the hepatic extraction of HEX is low, 2) the hepatic clearance is concentration independent up to 500 ng HEX/ml of perfusate, and 3) the plasma protein binding of HEX is significant over the dose range studied. HEX exhibits a low hepatic extraction ratio, allowing us to predict that its hepatic clearance may be limited upon HEX protein binding.