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Comprehensive Substrate Characterization of 22 Antituberculosis Drugs for Multiple Solute Carrier (SLC) Uptake Transporters In Vitro.

ABSTRACT: 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 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 ?M for organic cation transporter 1 (OCT1), OCT2, OCTN1, and OCTN2, respectively. Similarly, the K_m of prothionamide was 805.8 ± 23.4 ?M for OCT1, while the K_m values of isoniazid and amoxicillin for organic anion transporter 3 (OAT3) were 233.7 ± 14.1 and 161.4 ± 10.6 ?M, 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.

SUBMITTER: Parvez MM

PROVIDER: S-EPMC6125539 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Comprehensive Substrate Characterization of 22 Antituberculosis Drugs for Multiple Solute Carrier (SLC) Uptake Transporters In Vitro.

Parvez M M MM Kaisar Nazia N Shin Ho Jung HJ Lee Yoon Jae YJ Shin Jae-Gook JG

Antimicrobial agents and chemotherapy 20180827 9

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 et ...[more]

PMID: 30012768

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Project description:The human solute carrier (SLC) superfamily of transporters is comprised of over 400 membrane-bound proteins, and plays essential roles in a multitude of physiological and pharmacological processes. In addition, perturbation of SLC transporter function underlies numerous human diseases, which renders SLC transporters attractive drug targets. Common genetic polymorphisms in SLC genes have been associated with inter-individual differences in drug efficacy and toxicity. However, despite their tremendous clinical relevance, epidemiological data of these variants are mostly derived from heterogeneous cohorts of small sample size and the genetic SLC landscape beyond these common variants has not been comprehensively assessed. In this study, we analyzed Next-Generation Sequencing data from 141,456 individuals from seven major human populations to evaluate genetic variability, its functional consequences, and ethnogeographic patterns across the entire SLC superfamily of transporters. Importantly, of the 204,287 exonic single-nucleotide variants (SNVs) which we identified, 99.8% were present in less than 1% of analyzed alleles. Comprehensive computational analyses using 13 partially orthogonal algorithms that predict the functional impact of genetic variations based on sequence information, evolutionary conservation, structural considerations, and functional genomics data revealed that each individual genome harbors 29.7 variants with putative functional effects, of which rare variants account for 18%. Inter-ethnic variability was found to be extensive, and 83% of deleterious SLC variants were only identified in a single population. Interestingly, population-specific carrier frequencies of loss-of-function variants in SLC genes associated with recessive Mendelian disease recapitulated the ethnogeographic variation of the corresponding disorders, including cystinuria in Jewish individuals, type II citrullinemia in East Asians, and lysinuric protein intolerance in Finns, thus providing a powerful resource for clinical geneticists to inform about population-specific prevalence and allelic composition of Mendelian SLC diseases. In summary, we present the most comprehensive data set of SLC variability published to date, which can provide insights into inter-individual differences in SLC transporter function and guide the optimization of population-specific genotyping strategies in the bourgeoning fields of personalized medicine and precision public health.

Dataset Information

Comprehensive Substrate Characterization of 22 Antituberculosis Drugs for Multiple Solute Carrier (SLC) Uptake Transporters In Vitro.

Publications

Comprehensive Substrate Characterization of 22 Antituberculosis Drugs for Multiple Solute Carrier (SLC) Uptake Transporters <i>In Vitro</i>.

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