title: Inhibitory Interaction Potential of 22 Antituberculosis Drugs on Organic Anion and Cation Transporters of the SLC22A Family.
abstract: Twenty-two currently marketed antituberculosis drugs were comprehensively evaluated for their inhibitory effect on organic anionic transporter (OAT)- and organic cation transporter (OCT)-mediated uptake using stably transfected HEK293 cells in vitro We observed moderate to strong inhibitory effects on OAT1- and OAT3-mediated para-aminohippurate (PAH) uptake and OCT1- and OCT2-mediated N-methyl-4-phenylpylidinium acetate (MPP+) uptake. Ciprofloxacin, linezolid, para-aminosalicylic acid (PAS), and rifampin were observed to have strong inhibitory effects, with the concentrations for a 50% inhibitory effect (IC50s) being 35.1, 31.1, 37.6, and 48.1 μM, respectively, for OAT1 and >100, 21.9, 24.6, and 30.2 μM, respectively, for OAT3. Similarly, pyrazinamide, rifabutin, and levofloxacin were observed to have inhibitory effects, with IC50values being 36.5, 42.7, and 30.3 μM, respectively, for OCT1 and with the IC50value for PAS being 94.2 μM for OCT2. In addition, we used zidovudine and metformin as clinically prescribed substrates of OATs and OCTs, respectively, and zidovudine and metformin uptake was also strongly inhibited by the antituberculosis drugs. Among the tested drugs, the highest drug-drug interaction (DDI) indexes were found for PAS, which were 9.3 to 13.9 for OAT1 and 12.0 to 17.7 for OAT3, and linezolid, which were 1.18 to 2.15 for OAT1 and 1.7 to 3.01 for OAT3. Similarly, the DDI indexes of pyrazinamide and levofloxacin were 0.57 and 0.30, respectively, for OCT1, and the DDI index of PAS was 3.8 for OCT2, suggesting a stronger possibility (DDI index value cutoff, >0.1) of in vivo DDIs. This is the first comprehensive report of the inhibitory potential of anti-TB drugs on OAT- and OCT-mediated uptake of prototype and clinically prescribed substrate drugs in vitro, providing an ability to predict DDIs between anti-TB drugs and other coprescribed drugs in clinical studies in vivo.
authors.affiliation: Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea.
authors.forename: M Masud
authors.initials: MM
authors.lastname: Parvez
authors.affiliation: Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea.
authors.forename: Nazia
authors.initials: N
authors.lastname: Kaisar
authors.affiliation: Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea.
authors.forename: Ho Jung
authors.initials: HJ
authors.lastname: Shin
authors.affiliation: Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Republic of Korea.
authors.forename: Jin Ah
authors.initials: JA
authors.lastname: Jung
authors.affiliation: Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea phshinjg@inje.ac.kr.|Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Republic of Korea.
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism; D010131:Aminosalicylic Acid / Q000494:pharmacology; D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D002939:Ciprofloxacin / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D017136:Ion Transport / Q000187:drug effects; D007700:Kinetics; D064704:Levofloxacin / Q000494:pharmacology; D000069349:Linezolid / Q000494:pharmacology; D008687:Metformin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D050811:Octamer Transcription Factor-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D027362:Organic Anion Transport Protein 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors* / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D011718:Pyrazinamide / Q000494:pharmacology; D017828:Rifabutin / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology; D015215:Zidovudine / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: D000995:Antitubercular Agents; D050811:Octamer Transcription Factor-1; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C494165:POU2F1 protein, human; C491013:SLC22A2 protein, human; C114338:organic anion transport protein 3; D017828:Rifabutin; D011718:Pyrazinamide; D015215:Zidovudine; D010131:Aminosalicylic Acid; D002939:Ciprofloxacin; D064704:Levofloxacin; D008687:Metformin; D000069349:Linezolid; D015655:1-Methyl-4-phenylpyridinium; D012293:Rifampin