Pharmacokinetics and Metabolism of Delamanid, a Novel Anti-Tuberculosis Drug, in Animals and Humans: Importance of Albumin Metabolism In Vivo
| Autor: | Katsunori Sasahara, Yukihiro Hirao, Masakazu Shibata, Kazuyoshi Kitano, Ken Umehara, Noriyuki Koyama, Yoshihiko Shimokawa |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Metabolite Antitubercular Agents Pharmaceutical Science Pharmacology Biology Hydroxylation Rats Sprague-Dawley Mice chemistry.chemical_compound Dogs Cytochrome P-450 Enzyme System Pharmacokinetics In vivo Oral administration Albumins medicine Animals Humans Oxazoles Biotransformation Mice Inbred ICR CYP3A4 Albumin Metabolism Ketones Rats Isoenzymes Biochemistry chemistry Nitroimidazoles Female Delamanid Oxidation-Reduction medicine.drug |
| Zdroj: | Drug Metabolism and Disposition. 43:1267-1276 |
| ISSN: | 1521-009X 0090-9556 |
| DOI: | 10.1124/dmd.115.064527 |
| Popis: | 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. 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-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 three 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 eight metabolites after repeated oral dosing in humans, which indicated that M1 was the major metabolite. The overall metabolism of delamanid was qualitatively similar across nonclinical species and humans but was quantitatively different among the species. After repeated administration, the metabolites had much higher concentrations in dogs and humans than in rodents. The in vitro metabolic activity of albumin on delamanid probably caused the species differences observed. We determined that albumin metabolism is a key component of the pharmacokinetics and metabolism of delamanid. Nonhepatic formation of M1 and multiple separate pathways for metabolism of M1 suggest that clinically significant drug-drug interactions with delamanid and M1 are limited. |
| Databáze: | OpenAIRE |
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