Species differences in hydrolase activities toward OT-7100 responsible for different bioavailability in rats, dogs, monkeys and humans

OT-7100 (5-n-butyl-7-(3,4,5-trimethoxybenzoylamino)pyrazolo[1,5-a] pyrimidine) is an amide moiety-bearing pyrazolopyrimidine derivative with a potential analgesic effect. To determine the factors responsible for observed species differences in the bioavailability of this drug, human and experimental animal samples were used to investigate in vitro microsomal and cytosolic hydrolase activities in the liver and small intestine vis-a-vis the pharmacokinetics of OT-7100. The AUC0–t values of OT-7100 after oral administration in rats, dogs and monkeys were 0.163, 0.0383 and 0.00147 µg h ml−1 divided by mg kg−1, respectively. The bioavailabilities of OT-7100 after oral administration in rats, dogs and monkeys were 36, 17 and 0.3%, respectively. The plasma concentration–time profiles of intravenously administrated OT-7100 in rats, dogs and monkeys were similar. The hydrolase activities toward OT-7100 in liver microsomes or cytosol were approximately similar in rats, dogs, monkeys and humans. In contrast, hydrola...