SPECIES DIFFERENCE IN DRUG METABOLIZING ACTIVITY IN SMALL INTESTINE

Abstract

Species difference in nisoldipine metabolism was kinetically investigated to identify an animal model which can be predictable to the first pass metabolism in human intestine. Intestinal microsomes were prepared using a buffer containing 0.5 mg/ml trypsin inhibitor to prevent a loss of P450 activity during the preparation. The intrinsic clearance (Vmax/Km) estimated from the formation of two primary metabolites in the small intestinal microsomes was higher in monkeys, followed by humans, dogs, rats and guinea pigs. Noted that the CLint estimated in rat being a conventional animal was lower than that in humans. Some P450 inducers such as DEX were orally administered to rats to produce a mimic condition toward human small intestinal activity. Although DEX was the most potent inducer, the activity was only induced by a factor of 2. Since it is known that there are strain differences in metabolism activity and induction effect, the metabolic activity in several strains in addition to Wistar was also investigated. DA rats provided the highest small intestinal activity, and its activity increased by DEX was comparable to the CLint in human. The corresponding hepatic activity was similar in magnitude in all strains with and without DEX treatment. The small intestinal and hepatic activities in DEX-treated rats were inhibited by ketoconazole, CYP 3A inhibitor, and these estimated IC5o values suggested that CYP 3A would mainly be a responsible isoform for the small intestinal metabolism in DEX-treated DA rats.