Pre-clinical Characterization of Absorption, Distribution, Metabolism and Excretion Properties of TAK-063

Autor:	Miyako Sudo, Suguru Kato, Yoshihiko Tagawa, Junzo Takahashi, Kimio Tohyama, Akio Morohashi
Rok vydání:	2018
Předmět:	Male 0301 basic medicine Phosphodiesterase Inhibitors Metabolite Pharmacology Toxicology Intestinal absorption Rats Sprague-Dawley Excretion 03 medical and health sciences chemistry.chemical_compound Dogs 0302 clinical medicine Pharmacokinetics Oral administration Animals Cytochrome P-450 Enzyme Inhibitors Humans Rats Long-Evans Tissue Distribution Biotransformation ADME CYP3A4 Phosphoric Diester Hydrolases General Medicine Rats Bioavailability Pyridazines 030104 developmental biology Intestinal Absorption chemistry Pyrazoles Caco-2 Cells 030217 neurology & neurosurgery Antipsychotic Agents Half-Life Protein Binding
Zdroj:	Basic & Clinical Pharmacology & Toxicology. 122:577-587
ISSN:	1742-7835
DOI:	10.1111/bcpt.12964
Popis:	TAK-063 is currently being developed to treat schizophrenia. In this study, we investigated the absorption, distribution, metabolism and excretion (ADME) properties of TAK-063 using several paradigms. Following oral administration of TAK-063 at 0.3 mg/kg, bioavailability of TAK-063 was 27.4% in rats and 49.5% in dogs with elimination half-lives of 3.1 hr in rats and 3.7 hr in dogs. TAK-063 is a highly permeable compound without P-glycoprotein (P-gp) or breast cancer resistance protein substrate liability and can be readily absorbed into systemic circulation via the intestine. TAK-063 can also cross the blood-brain barrier. TAK-063 was metabolized mainly by CYP2C8 and CYP3A4/5, while incubation with human liver microsomes produced the major human metabolite, M-I as well as several unknown minor metabolites. Metabolism of TAK-063 to M-I occurs through hydroxylation of the mono-substituted pyrazole moiety. In vitro, TAK-063 was observed to inhibit CYP2C8, CYP2C19 and P-gp with IC50 values of 8.4, 12 and 7.13 μM, respectively. TAK-063 was primarily excreted in the faeces in rats and dogs with M-I as a predominant component. The pre-clinical data from these ADME studies demonstrate a favourable pharmacokinetic profile for TAK-063 with good brain distribution supporting the feasibility of targeting central nervous system regions involved in schizophrenia pathophysiology. TAK-063 has recently been investigated in a phase 2 clinical trial (NCT02477020).
Databáze:	OpenAIRE
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