Antitubercular Agent Delamanid and Metabolites as Substrates and Inhibitors of ABC and Solute Carrier Transporters
| Autor: | Hiroyuki Sasabe, Kenta Hashizume, Yoshihiro Ohzone, Masakazu Shibata, Yoshihiko Shimokawa, Eiji Kashiyama, Yusuke Hamasako, Ken Umehara |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
ATP Binding Cassette Transporter Subfamily B Organic anion transporter 1 Swine Metabolite Antitubercular Agents Biological Transport Active Organic Anion Transporters ATP-binding cassette transporter Pharmacology Clinical Therapeutics 030226 pharmacology & pharmacy Cell Line Kidney Tubules Proximal 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Tuberculosis Multidrug-Resistant medicine ATP Binding Cassette Transporter Subfamily G Member 2 Animals Humans Drug Interactions Pharmacology (medical) Oxazoles ATP Binding Cassette Transporter Subfamily B Member 11 Solute Carrier Proteins Organic cation transport proteins Errata biology Transporter Neoplasm Proteins Solute carrier family HEK293 Cells 030104 developmental biology Infectious Diseases chemistry Biochemistry Nitroimidazoles biology.protein ATP-Binding Cassette Transporters Efflux Delamanid Octamer Transcription Factor-1 medicine.drug |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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