Pharmacokinetics, oral bioavailability and metabolism of a novel isoquinolinone-based melatonin receptor agonist in rats.
Summary of "Pharmacokinetics, oral bioavailability and metabolism of a novel isoquinolinone-based melatonin receptor agonist in rats."
1. 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. 2. 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. 3. 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. 4. 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 the Biotechnology Research Institute, Hong Kong University of Science and Technology , Clear Water Bay, Kowloon, Hong Kong , China.
This article was published in the following journal.
Name: Xenobiotica; the fate of foreign compounds in biological systems
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22642804
- DOI: http://dx.doi.org/10.3109/00498254.2012.691186
Polyphyllin I (PPI), one of the steroidal saponins in Paris polyphylla, is a promising natural anticancer candidate. Although the anticancer activity of PPI has been well demonstrated, information reg...
Pimobendan is a benzimidazole-pyridazinone derivative, marketed as a racemic mixture for the management of canine heart failure. Pharmacokinetics of the enantiomers of pimobendan and its oral bioavail...
This study was to compare pharmacokinetics and bile transformation of R-enantiomer bambuterol with its racemate. Pharmacokinetics of R-enantiomer was investigated after single-dose intravenous and thr...
Tasimelteon is a novel dual melatonin receptor agonist and is the first treatment approved by the US Food and Drug Administration for Non-24-Hour Sleep-Wake Disorder. This study was conducted to asses...
The objectives were to document the pharmacokinetics of intravenous, enteric-coated oral and plain oral omeprazole in fasted horses and to investigate the impact of feeding on the bioavailability of a...
The primary focus of this five-year study will be to optimize the melatonin dosing regimen for synchronizing the body clocks of blind children to the 24-hour day.
Atypical antipsychotic medications, such as olanzapine, cause metabolic side effects, including weight gain, extra fat around the middle of the body, high blood sugar, and high cholesterol...
Morbid obesity (MO) is associated with several disorders such as hypertension, type 2 diabetes, dyslipemia and degenerative arthropathy that require pharmacological treatment. Drug bioavai...
Sleep disruptions are extremely common in high-risk critically ill patients. We want to analyse oral melatonin potentialities as a sedative and a free-radicals scavenger for critically ill...
Melatonin has been proposed as alternative to midazolam as a premedication in procedures preceding anaesthesia induction. The objective of this prospective, randomized, double-blind study ...
Medical and Biotech [MESH] Definitions
A biogenic amine that is found in animals and plants. In mammals, melatonin is produced by the PINEAL GLAND. Its secretion increases in darkness and decreases during exposure to light. Melatonin is implicated in the regulation of SLEEP, mood, and REPRODUCTION. Melatonin is also an effective antioxidant.
A family of G-protein-coupled receptors that are specific for and mediate the effects of MELATONIN. Activation of melatonin receptors has been associated with decreased intracellular CYCLIC AMP and increased hydrolysis of PHOSPHOINOSITIDES.
A potent and specific HIV protease inhibitor that appears to have good oral bioavailability.
Agents that aid or increase the action of the principle drug (DRUG SYNERGISM) or that affect the absorption, mechanism of action, metabolism, or excretion of the primary drug (PHARMACOKINETICS) in such a way as to enhance its effects.
A melatonin receptor subtype primarily found expressed in the BRAIN and RETINA.