caa a22 4500 477127754 CHVBK 20180405111654.0 cr unu---uuuuu 170330e19970801xx s 000 0 eng 10.1023/A:1012193010009 doi (NATIONALLICENCE)springer-10.1023/A:1012193010009 Hepatic Extraction of Hexarelin, a New Peptidic GH Secretagogue, in the Isolated Perfused Rat Liver [Elektronische Daten] [Marie Roumi, Sylvie Marleau, Muny Boghen, Magnus Nilsson, Patrick Du Souich, Huy Ong] 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 (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 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. Plenum Publishing Corporation, 1997 hexarelin nationallicence growth hormone releasing peptides nationallicence isolated perfused rat liver nationallicence hepatic extraction nationallicence in vitro plasma protein binding nationallicence Roumi Marie Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada aut Marleau Sylvie Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada aut Boghen Muny Pharmacia Upjohn, Stockholm, Sweden aut Nilsson Magnus Pharmacia Upjohn, Stockholm, Sweden aut Du Souich Patrick Department of Pharmacology, University of Montreal, Montreal, Quebec, Canada aut Ong Huy Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada aut Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/8(1997-08-01), 1008-1013 0724-8741 14:8<1008 1997 14 11095 https://doi.org/10.1023/A:1012193010009 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012193010009 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Roumi Marie Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada aut NATIONALLICENCE 700 1- Marleau Sylvie Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada aut NATIONALLICENCE 700 1- Boghen Muny Pharmacia Upjohn, Stockholm, Sweden aut NATIONALLICENCE 700 1- Nilsson Magnus Pharmacia Upjohn, Stockholm, Sweden aut NATIONALLICENCE 700 1- Du Souich Patrick Department of Pharmacology, University of Montreal, Montreal, Quebec, Canada aut NATIONALLICENCE 700 1- Ong Huy Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada aut NATIONALLICENCE 773 0- Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/8(1997-08-01), 1008-1013 0724-8741 14:8<1008 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer