IN-VITRO STABILITY AND INTESTINAL-ABSORPTION CHARACTERISTICS OF HEXAPEPTIDE ENDOTHELIN RECEPTOR ANTAGONISTS

Endothelins are potent vasoconstrictor peptides which have a wide rang e of tissue distribution and three receptor subtypes (ETA, ETB and ETC ). Among the linear hexapeptide ETA / ETB receptor antagonists, PD 145 065 (Ac-D-Bhg-L-Leu-L-Asp-L-Ile-L-Ile-L-Trp, Bhg = (10,11-dihydro-5H-d ibenzo [a,d] cyclohepten-5-yl)-Gly) and PD 156252 Ac-D-Bhg-L-Leu-L-Asp -L-Ile-(N-methyl)-L-Ile-L-Trp) were selected to evaluate the metabolic stability and intestinal absorption in the absence and/or in the pres ence of protease inhibitors. In vitro stability of both compounds was investigated in fresh plasma, lumenal perfusate, intestinal and liver homogenates. PD 156252 was more stable than PD 145065 in intestinal ti ssue homogenate (63.4 % vs. 20.5 % remaining) and liver homogenate (74 .4 % vs. 35.5 % remaining), while both compounds showed relatively goo d stability in the fresh plasma (94.5 % vs. 86.7 % remaining) and lume nal perfusate (85.8 % vs. 72.3 % remaining). The effect of protease in hibitors on the degradation of PD 145065 and PD 156252 was also invest igated. Amastatin, thiorphan, chymostatin and the mixture of these thr ee inhibitors were effective in reducing the degradation of both compo unds. The pharmacokinetic parameters of PD 156252, calculated by using a non-ompartmental model, were 6.95 min (terminal half-life), 191 mt (V-ss), and 25.5 mL/min (Cl-tot) after intravenous administration in r ats. The intestinal absorption of PD 156252 in rats was evaluated in t he absence and/or in the presence of protease inhibitors. The results indicate that the major elimination pathway of PD 156252 appears to be the biliary excretion and protease inhibitors increase the intestinal absorption of PD 156252 through increasing metabolic stability.