HEPATIC EXTRACTION OF HEXARELIN, A NEW PEPTIDIC GH SECRETAGOGUE, IN THE ISOLATED-PERFUSED RAT-LIVER

Purpose. To assess the hepatic extraction of hexarelin (HEX), a novel peptidyl GH secretagogue, in the isolated perfused rat model and docum ent the in vitro binding of HEX to plasma proteins using plasma from r ats, dogs, pigs, and humans. Methods. Rat liver was perfused in situ u sing a recirculating system. The recirculating perfusate: consisted of a Krebs Henseleit buffer containing 20% (v/v) prewashed bovine red bl ood cells, 1% albumin, and 1g/L dextrose. Three HEX concentrations of 5, 50, and 500 ng/ml were examined. In vitro plasma binding was determ ined by the ultrafiltration method. Results. The disappearance rate co nstant (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 = 0.3 45-0.401 ml/min/g liver, and E = 19-21% for the different concentratio ns of HEX. A linear increase in AUC (270-24334 min pmol/ml) was observ ed with increasing concentrations. Binding of HEX to plasma proteins o f 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 concentra tion-independent in the range between 0.003-3 mu M for the four specie s examined. Conclusions, These results show that 1) the hepatic extrac tion of HEX is low, 2) the hepatic clearance is concentration independ ent up to 500 ng HEX/ml of perfusate, and 3) the plasma protein bindin g of HEX is significant over the dose range studied. HEX exhibits a lo w hepatic extraction ratio, allowing us to predict that its hepatic cl earance may be limited upon HEX protein binding.