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 IS0042 were evaluated after intravenous administration (10 or 25 mg/kg) and oral administration (100 mg/kg) of the drug to rats. IS0042 showed moderate clearance (0.73-1.02 L/h/kg), large volume of distribution (1.76-3.16 L/kg) and long elimination half-life (3.11-6.04 h) after intravenous administration. The absolute oral bioavailability of IS0042 was relatively low (9.8-18.6%). Overall, these results provide important parameters for the further development of this novel class of melatoninergic ligands.
Division of Life Sciences, and Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
Jing
J
Zhu
Yueqing
Y
Hu
Maurice K C
MK
Ho
Yung H
YH
Wong
D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D018938:Caco-2 Cells; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044094:Receptors, Melatonin / Q000819:agonists*; D012995:Solubility
C578954:7-methoxy-6-(3-methoxybenzyloxy)-2-methylisoquinolin-1(2H)-one; D001798:Blood Proteins; D007546:Isoquinolines; D044094:Receptors, Melatonin