Endogenous Metabolites-Mediated Communication Between OAT1/OAT3 and OATP1B1 May Explain the Association Between SLCO1B1 SNPs and Methotrexate Toxicity.

Although OATP1B1 is not expressed in the kidney, polymorphisms in SLCO1B1 have been associated with methotrexate clearance or toxicity. This unexpected pharmacogenetic association may reflect remote communication between liver and kidney transporters. This study confirms the pharmacogenetic association with methotrexate toxicity in adult patients with hematological malignancies. Using a targeted urinary metabolomics approach, we identified 38 and 34 metabolites which were differentially excreted between wildtype and carriers of the c.388A>G or c.521T>C variant alleles, respectively, half of them being associated with methotrexate toxicity. These metabolites mainly consisted of fatty acid derivatives and microbiota catabolites, including glycine conjugates and other uremic toxins, all known OATs substrates. These results suggest that dysfunction of a transporter affects the excretion profile of endogenous or exogenous substrates, possibly through metabolite-mediated interactions involving other transport systems, even in distant organs. This opens the way for better comprehension of complex pharmacokinetics and transporter-mediated drug-drug or nutrient-drug interactions.