Dispositional characteristics of a tyrosine kinase inhibitor (RG 14620) in rats and rabbits following intravenous administration or dermal application

VK Khetarpal, PM Markham and JA Ziemniak

Rhone-Poulenc Rorer Central Research, Collegeville, PA 19426.

Based on its epidermal growth factor receptor-mediated tyrosine kinase inhibitory activity, (Z)-alpha-[(3,5-dichlorophenyl)methylene]-3- pyridylacetonitrile (RG 14620) is undergoing evaluation as a topical drug for psoriasis. Disposition studies were conducted in rats and rabbits, using [14C]RG 14620, primarily to investigate percutaneous absorption. Plasma radioactivity and the unchanged drug along with material balance were determined following intravenous administration (2.5 mg/kg) of a solution in PEG 400 or dermal application (50 mg/kg) of a 5% petrolatum ointment. Following an intravenous dose, initial (5- min) plasma radioactivity concentrations were comparable (approximately 1700 ng-eq/ml) in both species, but the decline was slower in rabbits. After dermal application, maximum plasma concentrations were attained at 12 hr in rats and 24 hr in rabbits, and corresponded to approximately 160 and 90 ng-eq/ml, respectively. Overall, the unchanged drug represented < 22% of the total plasma radioactivity in both species, suggesting extensive metabolism. In the rat, fecal route was the major route of excretion, whereas in the rabbit, urinary and fecal excretion contributed to about similar extent. Based on dose-adjusted ratios of plasma radioactivity AUC0-24 hr values, extent of percutaneous absorption appeared to be 1.9% in rats and 0.6% in rabbits. The estimates were 0.6% and 1.2%, respectively, when AUCs were determined for the unchanged drug in plasma. However, based on cumulative excretion of radioactivity up to 96 hr, percutaneous absorption was 12.0% in the rat and 2.0% in the rabbit. The differences in estimates of absorption were attributed to slow but continued absorption of the drug from skin, even after removal of the dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 22, Issue 2, pp. 216-223, 03/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics