XB-ART-55113Antimicrob Agents Chemother January 1, 2018; 62 (9):
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Comprehensive Substrate Characterization of 22 Antituberculosis Drugs for Multiple Solute Carrier (SLC) Uptake Transporters In Vitro.
The substrate potentials of antituberculosis drugs on solute carrier (SLC) transporters are not well characterized to date, despite a well-established understanding of their drug dispositions and pharmacokinetics. In this study, we investigated comprehensively the substrate potentials of the 22 currently available antituberculosis drugs for SLC family transporter-mediated uptake, using Xenopus laevis oocytes and stably transfected HEK-293 cells in vitro The result suggested that ethambutol, isoniazid, amoxicillin, and prothionamide act as novel substrates for the SLC transporters. In addition, in the presence of representative transporter inhibitors, the uptake of the antituberculosis drugs was markedly decreased compared with the uptake in the absence of inhibitor, suggesting involvement of the corresponding transporters. A cellular uptake study was performed, and the Km values of ethambutol were found to be 526.1 ± 15.6, 212.0 ± 20.1, 336.8 ± 20.1, and 455.0 ± 28 μM for organic cation transporter 1 (OCT1), OCT2, OCTN1, and OCTN2, respectively. Similarly, the Km of prothionamide was 805.8 ± 23.4 μM for OCT1, while the Km values of isoniazid and amoxicillin for organic anion transporter 3 (OAT3) were 233.7 ± 14.1 and 161.4 ± 10.6 μM, respectively. The estimated in vivo drug-drug interaction indexes from in vitro transporter inhibition kinetics for verapamil, probenecid, and ibuprofen against ethambutol, prothionamide, isoniazid, and amoxicillin were found to show potential for clinical drug interactions. In conclusion, this is the first study that demonstrated 22 antituberculosis drug interactions with transporters. This study will be helpful for mechanistic understanding of the disposition, drug-drug interactions, and pharmacokinetics of these antituberculosis drugs.
PubMed ID: 30012768
PMC ID: PMC6125539
Article link: Antimicrob Agents Chemother
Species referenced: Xenopus laevis
Genes referenced: pou2f1 pou2f2 slc22a4 slc22a5
References [+] :
Arakawa, Active intestinal absorption of fluoroquinolone antibacterial agent ciprofloxacin by organic anion transporting polypeptide, Oatp1a5. 2013, Pubmed, Xenbase