Relative contribution of the gut, liver, and lung to the first-pass hydrolysis (bioactivation) of orally administered 14C-fosinopril sodium in dogs. In vivo and in vitro studies

RA Morrison, SM Singhvi, AE Peterson, DA Pocetti and BH Migdalof

Squibb Institute for Medical Research, Princeton, NJ 08542-4000.

The relative contribution of the gut, liver, and lung to the first-pass hydrolysis (bioactivation) of the orally administered prodrug, fosinopril sodium (FS), to the active angiotensin-converting enzyme (ACE) inhibitor, SQ 27,519 (S), was determined. Two dogs each received 14C-FS by the following routes of administration: oral, intraportal, and intra-arterial. Extraction ratios (E) for the gut and liver were calculated based on the relative ratios of the AUC of FS in arterial plasma after administration of FS by various routes. The high intrinsic capability of the gut and liver to hydrolyze FS was reflected by E values which ranged from 69 to 91%. Since the gut is the first site after an oral dose, its contribution to the overall first-pass hydrolysis (greater than 75% of the absorbed dose) was estimated to be significantly greater than that of the liver (less than 25% of the absorbed dose). Concentrations of FS were similar in central arterial and venous plasma after a steady state arterial infusion of 14C-FS, indicating that the lung is apparently not a site of prodrug hydrolysis. This conclusion was consistent with the results of in vitro studies that indicated the following order of esterase activity: liver = kidney much greater than small intestine greater than blood, aorta, and lung. When data from in vitro studies were extrapolated to the in vivo situation, the blood itself was not a significant site for hydrolysis of FS in dogs. Based on the body clearance of FS (approximately 30 ml/min/kg) estimated after the intra-arterial route, roughly 50% of the systemic hydrolysis of the prodrug appears to occur at extrahepatic site(s), such as the kidney.

Volume 18, Issue 2, pp. 253-257, 03/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics

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