CYP3A5 AND CYCLOSPORINE/TACROLIMUS RENAL CLEARANCE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The calcineurin inhibitors, cyclosporine and tacrolimus, have proven to be essential to the prevention of graft rejection following solid organ transplantation. In terms of metabolism, these drugs are substrates for cytochromes P450 3A4 and 3A5 (CYP3A4/3A5). It has been shown that other organs also contribute to the metabolism and transport of cyclosporine and tacrolimus, such as the gut and kidney. Amongst the many cyclosporine metabolites produced, CYP3A5 highly contributes to the production of the metabolites AM9 and to a lesser extent AM19. However, CYP3A5 does not exhibit product selectivity towards tacrolimus and contributes to the formation of all of its metabolites. CYP3A5 displays genetic polymorphisms in the general population. These inter-individual differences have shown significant variability in the metabolism of calcineurin inhibitors. It has been shown that subjects that posses at least one allele for CYP3A5*1 have a higher clearance of both drugs, than CYP3A5*3*3 homozygotes. Of particular interest, is that CYP3A5 is found in the kidney, liver and gut, where as CYP3A4 is found in the liver and the gut only. We hypothesize that via quantification of the parent drug and metabolites in the urine, we can see the contribution of genetic differences in CYP3A5 to the renal formation clearance of cyclosporine metabolites (AM1c9, AM9 and AM19) and to the total renal clearance of tacrolimus. This genetically based difference in "local" metabolism may contribute to inter-individual differences in the risk of calcineurin inhibitor induced nephrotoxicity.