title: Antitubercular Agent Delamanid and Metabolites as Substrates and Inhibitors of ABC and Solute Carrier Transporters.
abstract: Delamanid (Deltyba, OPC-67683) is the first approved drug in a novel class of nitro-dihydro-imidazooxazoles developed for the treatment of multidrug-resistant tuberculosis. Patients with tuberculosis require treatment with multiple drugs, several of which have known drug-drug interactions. Transporters regulate drug absorption, distribution, and excretion; therefore, the inhibition of transport by one agent may alter the pharmacokinetics of another, leading to unexpected adverse events. Therefore, it is important to understand how delamanid affects transport activity. In the present study, the potencies of delamanid and its main metabolites as the substrates and inhibitors of various transporters were evaluated in vitro Delamanid was not transported by the efflux ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp; MDR1/ABCB1) and breast cancer resistance protein (BCRP/ABCG2), solute carrier (SLC) transporters, organic anion-transporting polypeptides, or organic cation transporter 1. Similarly, metabolite 1 (M1) was not a substrate for any of these transporters except P-gp. Delamanid showed no inhibitory effect on ABC transporters MDR1, BCRP, and bile salt export pump (BSEP; ABCB11), SLC transporters, or organic anion transporters. M1 and M2 inhibited P-gp- and BCRP-mediated transport but did so only at the 50% inhibitory concentrations (M1, 4.65 and 5.71 μmol/liter, respectively; M2, 7.80 and 6.02 μmol/liter, respectively), well above the corresponding maximum concentration in plasma values observed following the administration of multiple doses in clinical trials. M3 and M4 did not affect the activities of any of the transporters tested. These in vitro data suggest that delamanid is unlikely to have clinically relevant interactions with drugs for which absorption and disposition are mediated by this group of transporters.
authors.affiliation: Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan Sasabe.Hiroyuki@otsuka.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sasabe
authors.affiliation: Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Shimokawa
authors.affiliation: Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Shibata
authors.affiliation: ADME & Toxicology Research Institute, Sekisui Medical Co., Ltd., Ibaraki, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Hashizume
authors.affiliation: ADME & Toxicology Research Institute, Sekisui Medical Co., Ltd., Ibaraki, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Hamasako
authors.affiliation: ADME & Toxicology Research Institute, Sekisui Medical Co., Ltd., Ibaraki, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ohzone
authors.affiliation: Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kashiyama
authors.affiliation: Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Umehara
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D001693:Biological Transport, Active / Q000187:drug effects; D002460:Cell Line; D004347:Drug Interactions / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology; D009363:Neoplasm Proteins / Q000378:metabolism*; D009593:Nitroimidazoles / Q000378:metabolism / Q000494:pharmacology*; D050811:Octamer Transcription Factor-1 / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism*; D010080:Oxazoles / Q000378:metabolism / Q000494:pharmacology*; D000070590:Solute Carrier Proteins / Q000378:metabolism*; D013552:Swine; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*
chemical_list: C513055:ABCB1 protein, human; C093491:ABCB11 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000995:Antitubercular Agents; D009363:Neoplasm Proteins; D009593:Nitroimidazoles; C516022:OPC-67683; D050811:Octamer Transcription Factor-1; D027361:Organic Anion Transporters; D010080:Oxazoles; C494165:POU2F1 protein, human; D000070590:Solute Carrier Proteins