title: Evaluation ofpara-Aminosalicylic Acid as a Substrate of Multiple Solute Carrier Uptake Transporters and Possible Drug Interactions with Nonsteroidal Anti-inflammatory DrugsIn Vitro.
abstract: para-Aminosalicylic acid (PAS) is a second-line antituberculosis drug that has been used to treat multidrug-resistant and extensively drug-resistant tuberculosis for more than 60 years. Renal secretion and glomerular filtration are the major pathways for the elimination of PAS. We comprehensively studied PAS transport by using cell lines that overexpressed various transporters and found that PAS acts as a novel substrate of an organic anionic polypeptide (OATP1B1), organic cationic transporters (OCT1 and OCT2), and organic anion transporters (OAT1 and OAT3) but is not a substrate of any ATP-binding cassette (ABC) transporters. Net PAS uptake was measured, and the transport affinities (Kmvalues) for OATP1B1, OCT1, OCT2, OAT1, and OAT3 were found to be 50.0, 20.3, 28.7, 78.1, and 100.1 μM, respectively. The net uptake rates suggested that renal OAT1 and OAT3 play relatively major roles in PAS elimination. The representative inhibitors rifampin for OATP1B1, probenecid for OAT1 and OAT3, and verapamil for OCT1 and OCT2 greatly inhibited PAS uptake, suggesting that PAS is dependent on multiple transporters for uptake. We also evaluated nonsteroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), and metformin for the inhibition of PAS uptake via these transporters. Half-maximal (50%) inhibitory concentrations (IC50s) were kinetically determined and used to predict the drug-drug interactions (DDIs) affecting these transporters' activity toward PAS. We found that rifampin, probenecid, ibuprofen, naproxen, cimetidine, and quinidine each exhibited a significant potential forin vivoDDIs with PAS. In this study, PAS was found to be a novel substrate of several transporters, and drugs that inhibit these transporters can reduce PAS elimination.
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: 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: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D010131:Aminosalicylic Acid / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002927:Cimetidine / Q000494:pharmacology; D004347:Drug Interactions / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D027381:Liver-Specific Organic Anion Transporter 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009288:Naproxen / 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*; D000075102:Organic Cation Transporter 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011339:Probenecid / Q000494:pharmacology; D054328:Proton Pump Inhibitors / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000995:Antitubercular Agents; D027381:Liver-Specific Organic Anion Transporter 1; D050811:Octamer Transcription Factor-1; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D000075102:Organic Cation Transporter 2; C494165:POU2F1 protein, human; D054328:Proton Pump Inhibitors; C491013:SLC22A2 protein, human; C503999:SLCO1B1 protein, human; C114338:organic anion transport protein 3; D009288:Naproxen; D010131:Aminosalicylic Acid; D002927:Cimetidine; D014700:Verapamil; D011802:Quinidine; D011339:Probenecid; D012293:Rifampin; D007052:Ibuprofen
keywords: antituberculosis drug; drug-drug interactions; membrane transporter