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

Drug Research
M NishiharaSatoru Asahi

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 formatio...Continue Reading

Citations

Aug 26, 2014·The Journal of Steroid Biochemistry and Molecular Biology·Alex Odermatt, Petra Klusonova
Apr 3, 2012·Ground Water·Khayyun A Rahi, Todd Halihan

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