title: Main metabolic pathways of TAK-802, a novel drug candidate for voiding dysfunction, in humans: the involvement of carbonyl reduction by 11β-hydroxysteroid dehydrogenase 1.
abstract: To investigate species differences in the metabolism of TAK-802, in vitro and in vivo metabolic profiles were compared between humans and animals. TAK-802 was mainly metabolized to M-I, M-II, M-III and M-IV in human and animal liver microsomes. Especially the M-IV formation in humans was greater than that in animals. Likewise, M-IV was detected to a lower extent in the plasma and excreta of animals administered with TAK-802, whereas the AUC0-48 h of M-IV was approximately five-fold higher than that of TAK-802 in human plasma. These results indicate that the in vitro metabolic profile reflects the in vivo condition. Thus, to identify the metabolic pathway of TAK-802 in humans, the responsible enzyme to form M-IV was elucidated in vitro. Since M-IV is a reductive metabolite formed in microsomes, the possibility of involvement of 11β-hydroxysteroid dehydrogenase (11β-HSD), a carbonyl reductase located in microsomes, was first investigated. Consequently, M-IV formation was confirmed by incubation with human 11β-HSD1-expressing microsomes and was concentration-dependently inhibited by glycyrrhetinic acid, an inhibitor for 11β-HSD enzymes, indicating the involvement of 11β-HSD1 in the M-IV formation. In contrast, little M-IV formation was observed using rat 11β-HSD1, suggesting species differences between humans and rats. In addition, M-II was formed via M-IV, not via M-I and the CYP identification studies revealed that both M-I formation from TAK-802 and M-II formation from M-IV were mainly catalyzed by CYP3A4. In conclusion, 11β-HSD1 and CYP3A4 are principally responsible for the metabolism of TAK-802 in humans and 11β-HSD1 may be responsible for the observed species difference.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Nishihara
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Takahashi
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kondo
authors.affiliation: Takeda Development Center Japan, Pharmaceutical Development Division, Takeda Pharmaceutical Company Limited, Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Mouri
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Asahi
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism*; D000818:Animals; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006034:Glycyrrhetinic Acid / Q000008:administration & dosage / Q000494:pharmacology; D000882:Haplorhini; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D011758:Pyrroles / Q000493:pharmacokinetics*; D015363:Quinolones / Q000493:pharmacokinetics*; D051381:Rats; D013045:Species Specificity
chemical_list: D011758:Pyrroles; D015363:Quinolones; C496138:8-(3-(1-((3-fluorophenyl)methyl)-4-piperidinyl)-1-oxopropyl)-1,2,5,6-tetrahydro-4H-pyrrolo(3,2,1-ij)quinolin-4-one; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D051544:Cytochrome P-450 CYP3A; D006034:Glycyrrhetinic Acid