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

• Published in: Xenobiotica 2012-11, Vol.42 (11), p.1138-1150
• Main Authors: Zhu, Jing, Hu, Yueqing, Ho, Maurice K. C, Wong, Yung H.
• Format: Article
• Language: English
• Subjects: Administration, Intravenous; Administration, Oral; Animals; Biological Availability; Blood Proteins - metabolism; Caco-2 Cells; Dogs; Drug Evaluation, Preclinical; Humans; IS0042; Isoquinolines - administration & dosage; Isoquinolines - metabolism; Isoquinolines - pharmacokinetics; Madin Darby Canine Kidney Cells; Male; Melatonin receptor agonist; metabolism; Microsomes, Liver - metabolism; oral bioavailability; pharmacokinetics; Rats; Rats, Sprague-Dawley; Receptors, Melatonin - agonists; Solubility
• ISSN: 0049-8254; 1366-5928
• DOI: 10.3109/00498254.2012.691186

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.