Hepatic clearance of ONO-5046, a novel neutrophil elastase inhibitor, in rats and in the rat perfused liver

The hepatic clearance of ONO-5046 (N-[2-[4-(2,2-dimethylpropionyloxy)phenyl sulphonyl-amino]benzoyl]aminoacetic acid), a low-molecular-weight neutrophi l elastase inhibitor, has been investigated in rats and in the rat perfused liver. This ester was easily hydrolysed to its inactive metabolite EI-601 (N-[2-[( 4-hydroxy-phenyl)sulphonylamino]benzoyl]aminoacetic acid) in liver homogena te and in erythrocytes suspension in-vitro. On the other hand, it was stabl e in biological media such as plasma and whole blood, which contain plasma proteins. Scatchard plot analysis of ONO-5046 binding to bovine serum album in (BSA) in-vitro indicated that the association constant (K) and number of binding sites (n) were 6.91 x 10(4) (M-1) and 4.33, respectively. Thus, ON O-5046 (100 mu M) would bind to plasma proteins to an extent >99% at physio logical plasma-protein concentrations, The total plasma clearance of ONO-50 46 in rats was constant (approximately 9 mL min(-1) kg(-1)) under different steady-state plasma concentrations (5-50 mu M) a value equivalent to the h epatic clearance. In the rat perfused liver, the hepatic extraction ratio o f ONO-5046 was significantly reduced by adding BSA to the dosing solution, Thus, the relatively low hepatic clearance of ONO-5046, which has an ester linkage in its structure and is naturally susceptible to enzymatic hydrolys is, was found to be because of the extremely high protein-binding of the co mpound.