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 lg/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 (t1/2), clearance (Cl), and hepatic extraction ratio (E) were: K = 0.013-0.014 min-1, t1/2 = 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 microM 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.
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 lg/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 (t1/2), clearance (Cl), and hepatic extraction ratio (E) were: K = 0.013-0.014 min-1, t1/2 = 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 microM 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.
Authors: M Seno; Y Seino; Y Takemura; S Nishi; H Ishida; N Kitano; H Imura; T Taminato; S Matsukura Journal: Can J Physiol Pharmacol Date: 1985-01 Impact factor: 2.273
Authors: S G Cella; V Locatelli; M Poratelli; V De Gennaro Colonna; B P Imbimbo; R Deghenghi; E E Müller Journal: Peptides Date: 1995 Impact factor: 3.750
Authors: E Ghigo; E Arvat; L Gianotti; B P Imbimbo; V Lenaerts; R Deghenghi; F Camanni Journal: J Clin Endocrinol Metab Date: 1994-03 Impact factor: 5.958
Authors: A D Howard; S D Feighner; D F Cully; J P Arena; P A Liberator; C I Rosenblum; M Hamelin; D L Hreniuk; O C Palyha; J Anderson; P S Paress; C Diaz; M Chou; K K Liu; K K McKee; S S Pong; L Y Chaung; A Elbrecht; M Dashkevicz; R Heavens; M Rigby; D J Sirinathsinghji; D C Dean; D G Melillo; A A Patchett; R Nargund; P R Griffin; J A DeMartino; S K Gupta; J M Schaeffer; R G Smith; L H Van der Ploeg Journal: Science Date: 1996-08-16 Impact factor: 47.728