Comprehensive substrate characterization of 22 antituberculosis drugs for multiple solute carrier (SLC) uptake transporters, in vitro [PublishAheadOfPrint]

Substrate potential of antituberculosis drugs on 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 solute carrier (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 K_m 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 OCT1, OCT2, OCTN1, and OCTN2, respectively. Similarly, the K_m of prothionamide was 805.8 ± 23.4 μM for OCT1, while the K_m values of isoniazid and amoxicillin for 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 be potential for clinical drug interactions. In conclusion, this is the first study that, demonstrated 22 antituberculosis drugs interactions with transporters. This study will be helpful for mechanistic understanding of the disposition, drug-drug interactions and pharmacokinetics of these antituberculosis drugs.

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