Evaluation of para -Aminosalicylic Acid as a Substrate of Multiple Solute Carrier Uptake Transporters and Possible Drug Interactions with Nonsteroidal Anti-inflammatory Drugs In Vitro

• Published in: Antimicrobial agents and chemotherapy 2017-05, Vol.61 (5)
• Main Authors: Parvez, M Masud, Shin, Ho Jung, Jung, Jin Ah, Shin, Jae-Gook
• Format: Article
• Language: English
• Subjects: Aminosalicylic Acid; Aminosalicylic Acid - metabolism; Aminosalicylic Acid - pharmacokinetics; Aminosalicylic Acid - pharmacology; Anti-Inflammatory Agents, Non-Steroidal; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Antitubercular Agents; Antitubercular Agents - metabolism; Antitubercular Agents - pharmacokinetics; Antitubercular Agents - pharmacology; ATP-Binding Cassette Transporters - metabolism; Biological Transport - drug effects; Biological Transport - physiology; Cell Line; Cimetidine - pharmacology; Drug Interactions - physiology; HEK293 Cells; Humans; Ibuprofen - pharmacology; Liver-Specific Organic Anion Transporter 1; Mycobacterium; Naproxen - pharmacology; Octamer Transcription Factor-1; Octamer Transcription Factor-1 - antagonists & inhibitors; Octamer Transcription Factor-1 - metabolism; Organic Anion Transport Protein 1; Organic Anion Transport Protein 1 - antagonists & inhibitors; Organic Anion Transport Protein 1 - metabolism; Organic Anion Transporters, Sodium-Independent; Organic Anion Transporters, Sodium-Independent - antagonists & inhibitors; Organic Anion Transporters, Sodium-Independent - metabolism; Organic Cation Transporter 2; Organic Cation Transporter 2 - antagonists & inhibitors; Organic Cation Transporter 2 - metabolism; Pharmacology; Probenecid - pharmacology; Proton Pump Inhibitors - pharmacology; Quinidine - pharmacology; Rifampin - pharmacology; Solute Carrier Organic Anion Transporter Family Member 1b1 - antagonists & inhibitors; Solute Carrier Organic Anion Transporter Family Member 1b1 - metabolism; Verapamil - pharmacology
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.02392-16

-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 ( values) 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 (IC s) 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 for DDIs 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.