title: Delamanid does not inhibit or induce cytochrome p450 enzymes in vitro.
abstract: Delamanid is a new drug for the treatment of multidrug-resistant tuberculosis. Individuals who are co-infected with human immunodeficiency virus and Mycobacterium tuberculosis may require treatment with a number of medications that might interact significantly with the CYP enzyme system as inhibitors or inducers. It is therefore important to understand how drugs in development for the treatment of tuberculosis will affect CYP enzyme metabolism. The ability of delamanid to inhibit or induce CYP enzymes was investigated in vitro using human liver microsomes or human hepatocytes. Delamanid (100 µM) had little potential for mechanism-based inactivation on eight CYP isoforms (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). Delamanid's metabolites were noted to inhibit the metabolism of some CYP isoforms, but these effects were observed only at metabolite concentrations that were well above those observed in human plasma during clinical trials. Delamanid (≤10 µM) did not induce CYP1A2, CYP2C9, and CYP3A4 activities in human hepatocytes, and there were no increases in CYP1A2, CYP2B6, CYP2C9, and CYP3A4 mRNA levels. Taken together, these data suggest that delamanid is unlikely to cause clinically relevant drug-drug interactions when co-administered with products that are metabolized by the CYP enzyme system.
authors.affiliation: Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Shimokawa
authors.forename: Katsunori
authors.initials: K
authors.lastname: Sasahara
authors.forename: Noriaki
authors.initials: N
authors.lastname: Yoda
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mizuno
authors.forename: Ken
authors.initials: K
authors.lastname: Umehara
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004347:Drug Interactions; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009593:Nitroimidazoles / Q000494:pharmacology*; D010080:Oxazoles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D000995:Antitubercular Agents; D009593:Nitroimidazoles; C516022:OPC-67683; D010080:Oxazoles; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System