Pharmacokinetics, oral bioavailability and metabolism of a novel isoquinolinone-based melatonin receptor agonist in rats.

7-Methoxy-6-(3-methoxy-benzyloxy)-2-methylisoquinolin-1(2H)-one (named as IS0042) is a newly identified melatoninergic agonist which exhibits selectivity to the type 2 melatonin receptor. Here, we examined the in vitro and in vivo pharmacokinetics properties of IS0042 in rats.IS0042 was considerably lipophilic with a modest aqueous solubility of 27.3 µg/mL. It was stable in simulated gastrointestinal fluid, and readily penetrated across differentiated Caco-2 cell model of intestinal barrier, suggesting good oral absorption.IS0042 underwent metabolism in rat intestinal and liver microsomes with an in vitro half-life of 367.5 ± 36.6 and 17.5 ± 2.7 min, respectively. Metabolite identification suggested that the major biotransformation pathways included the cleavage of ether bond, hydroxylation and demethylation. The same metabolites were also present in blood circulation following oral administration, indicating a good correlation between in vitro and in vivo metabolism.The pharmacokinetics parameters of IS0...