CYP3A5 AND CYCLOSPORINE/TACROLIMUS RENAL CLEARANCE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 钙调磷酸酶抑制剂，环孢素和他克莫司，已被证明是必不可少的，以防止移植物排斥反应后实体器官移植。在代谢方面，这些药物是细胞色素P450 3A 4和3A 5（CYP 3A 4/3A 5）的底物。已经表明，其他器官也有助于环孢霉素和他克莫司的代谢和转运，例如肠道和肾脏。在产生的许多环孢菌素代谢物中，CYP 3A 5高度促进代谢物AM 9的产生，并在较小程度上促进AM 19的产生。然而，CYP 3A 5对他克莫司没有表现出产物选择性，并有助于其所有代谢产物的形成。CYP 3A 5在一般人群中显示遗传多态性。这些个体间差异显示钙调磷酸酶抑制剂代谢的显著变异性。研究表明，携带至少一个CYP 3A 5 *1等位基因的受试者对两种药物的清除率高于CYP 3A 5 *3*3纯合子。特别令人感兴趣的是，CYP 3A 5存在于肾脏、肝脏和肠道中，而CYP 3A 4仅存在于肝脏和肠道中。我们假设，通过定量尿液中的母体药物和代谢物，我们可以看到CYP 3A 5的遗传差异对环孢素代谢物（AM 1c 9、AM 9和AM 19）的肾脏形成清除率和他克莫司的总肾脏清除率的贡献。这种基于遗传的“局部”代谢差异可能导致钙调磷酸酶抑制剂诱导肾毒性风险的个体间差异。

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.