Inhibitory Interaction Potential of 22 Antituberculosis Drugs on Organic Anion and Cation Transporters of the SLC22A Family.

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Parvez MM, Kaisar N, Shin HJ, Jung JA, Shin JG

Inhibitory Interaction Potential of 22 Antituberculosis Drugs on Organic Anion and Cation Transporters of the SLC22A Family.

Antimicrob Agents Chemother. 2016 Oct 21;60(11):6558-6567. doi: 10.1128/AAC.01151-16. Print 2016 Nov.

PubMed ID

27550354 [ View in PubMed

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Abstract

Twenty-two currently marketed antituberculosis drugs were comprehensively evaluated for their inhibitory effect on organic anionic transporter (OAT)- and organic cation transporter (OCT)-mediated uptake using stably transfected HEK293 cells in vitro We observed moderate to strong inhibitory effects on OAT1- and OAT3-mediated para-aminohippurate (PAH) uptake and OCT1- and OCT2-mediated N-methyl-4-phenylpylidinium acetate (MPP(+)) uptake. Ciprofloxacin, linezolid, para-aminosalicylic acid (PAS), and rifampin were observed to have strong inhibitory effects, with the concentrations for a 50% inhibitory effect (IC50s) being 35.1, 31.1, 37.6, and 48.1 muM, respectively, for OAT1 and >100, 21.9, 24.6, and 30.2 muM, respectively, for OAT3. Similarly, pyrazinamide, rifabutin, and levofloxacin were observed to have inhibitory effects, with IC50 values being 36.5, 42.7, and 30.3 muM, respectively, for OCT1 and with the IC50 value for PAS being 94.2 muM for OCT2. In addition, we used zidovudine and metformin as clinically prescribed substrates of OATs and OCTs, respectively, and zidovudine and metformin uptake was also strongly inhibited by the antituberculosis drugs. Among the tested drugs, the highest drug-drug interaction (DDI) indexes were found for PAS, which were 9.3 to 13.9 for OAT1 and 12.0 to 17.7 for OAT3, and linezolid, which were 1.18 to 2.15 for OAT1 and 1.7 to 3.01 for OAT3. Similarly, the DDI indexes of pyrazinamide and levofloxacin were 0.57 and 0.30, respectively, for OCT1, and the DDI index of PAS was 3.8 for OCT2, suggesting a stronger possibility (DDI index value cutoff, >0.1) of in vivo DDIs. This is the first comprehensive report of the inhibitory potential of anti-TB drugs on OAT- and OCT-mediated uptake of prototype and clinically prescribed substrate drugs in vitro, providing an ability to predict DDIs between anti-TB drugs and other coprescribed drugs in clinical studies in vivo.

DrugBank Data that Cites this Article

Drugs

Levofloxacin

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Levofloxacin	Solute carrier family 22 member 1	Protein	Humans	Unknown	Inhibitor	Details
Levofloxacin	Solute carrier family 22 member 2	Protein	Humans	Unknown	Inhibitor	Details
Linezolid	Solute carrier family 22 member 6	Protein	Humans	No	Inhibitor	Details
Linezolid	Solute carrier family 22 member 8	Protein	Humans	No	Inhibitor	Details