Delamanid, a new anti-tuberculosis drug, is metabolized to M1, a unique metabolite formed by cleavage of the 6-nitro-2,3-dihydroimidazo [2,1-b] oxazole moiety, in plasma albumin in vitro (Shimokawa et al., 2015). The metabolic activities in dogs and humans are higher than those in rodents. In this study, we characterized the pharmacokinetics and metabolism of delamanid in animals and humans. Eight metabolites (M1 to M8) produced by cleavage of the imidazooxazole moiety of delamanid were identified in the plasma after repeated oral administration by liquid chromatography-mass spectrometry analysis. Delamanid was initially catalyzed to M1 and subsequently metabolized by 3 separate pathways, which suggested that M1 is a crucial starting point. The major pathway in humans was hydroxylation of the oxazole moiety of M1 to form M2 and then successive oxidation to the ketone form (M3) mainly by CYP3A4. M1 had the highest exposure among the 8 metabolites after repeated oral dosing in humans, which indicated that M1 was the major metabolite. 

 

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