Impact of the loss of slc43a3 on 6-mercaptopurine absorption and tissue distribution in mice.

Abstract

6-Mercaptopurine (6-MP) is a nucleobase analog used in the therapy of acute lymphoblastic leukemia and inflammatory bowel disease. It is associated with numerous side effects including myelotoxicity, hepatotoxicity, and gastrointestinal complications, which can lead to patient adherence issues or discontinuation of treatment. This is further complicated by the wide variability in plasma levels of 6-MP and the therapeutic response to a standard dose. Although a number of enzyme polymorphisms have been linked to therapeutic response, it is unclear what factors underlie the variability in plasma levels. We have established that SLC43A3-encoded equilibrative nucleobase transporter 1 mediates the transport of 6-MP into cells in both mice and humans. To determine whether this transporter is critical for 6-MP absorption and biodistribution, we examined the effect of the genetic deletion of slc43a3 in mice on the absorption and tissue distribution of orally administered 6-MP. A high-performance liquid chromatography method was developed to measure tissue levels of 6-MP and its key metabolites, 6-methylmercaptoprine, 6-thiourate, and 6-thioguanine nucleotides. The results of this study show that loss of slc43a3 dramatically reduces the absorption of 6-MP from the gastrointestinal tract and attenuates the levels achieved in peripheral tissues. Furthermore, the loss of slc43a3 decreases the tissue:blood concentration ratios of 6-MP and its metabolites, particularly in those tissues that show high levels of expression of slc43a3, such as the heart and lungs. Therefore, it is possible that differences in SLC43A3 expression in humans may contribute to the variability seen in 6-MP plasma levels and therapeutic response. SIGNIFICANCE STATEMENT: The loss of slc43a3 in mice dramatically reduces the absorption and the biodistribution of the chemotherapeutic drug 6-mercaptopurine. These data suggest that variations in SLC43A3 expression in humans may contribute to the variability in plasma levels that have been reported when using this drug therapeutically.