The role of transporters in nephrotoxicity: An investigation from the bench to populations-based studies.

摘要

Renal transporters are primary modulators of drug disposition and elimination. The goals of this dissertation are: (1) to understand the role of renal transporters and genetic variation in renal transporters in disease through epidemiological studies and genetic association studies; (2) to characterize the role of transporters and assess the contribution of genetic variation in drug transport and cytotoxicity through functional experimental studies, (3) to identify and predict selective inhibitors of OAT1 and OAT3 through high throughput screening and computational modeling.;Our epidemiological study of tenofovir associated renal insufficiency demonstrates that tenofovir is associated with mild decline in renal function and that HIV therapy, in general, may improve renal function in women with pre-existing renal impairment. Functional studies demonstrate that SLC22A6 is a primary transporter for tenofovir and adefovir uptake in the renal proximal tubule. We found that rare variants in SLC22A6 may play a role in differential transport and cytotoxicity of tenofovir and adefovir. A genetic association study using DNA from 565 children with pediatric leukemia on methotrexate therapy demonstrated that in 8 candidate transporter genes chosen, 11 single nucleotide polymorphisms (SNPs) out of 44 SNPs in ABCC1, ABCC2, ABCC4, ABCG2, and SLC22A8 were significantly associated with changes in glomerular filtration rate(GFR) post-methotrexate. Haplotype blocks of the ABCG2 were found to be significantly associated with changes in GFR after methotrexate treatment. Findings from our chemo-informatics screening study suggest that SLC22A6 and SLC22A8 molecular interactors vary in structure and that small changes in electrostatics and steric effects can drastically change the inhibition activity of SLC22A6 and SLC22A8. A number of non-selective and selective inhibitors were identified. SAR studies identified several chemical descriptors unique to OAT1 and OAT3 interacting molecules.;This dissertation provides a unique look at drug-induced nephrotoxicity from the vantage of pharmacogenetic variation in the SLC22A6 and SLC22A8 transporters. It sets the stage for investigations where other genes involved in the nephrotoxicity pathways of these drugs may be investigated. It is our hope that insights from this dissertation can be further extended to other transporters in the SLC22 family and may inform clinical decisions in the future.