INSERM, UMR S-850, Limoges, France.
Transplantation. 2011 Mar 27;91(6):652-6. doi: 10.1097/TP.0b013e31820ae4ac.
CYP3A5 genotyping might be useful to guide tacrolimus and sirolimus dosing. The aim of this study was to assess the influence of CYP3A5 polymorphism on everolimus metabolism and pharmacokinetics.
We investigated the effect of CYP3A5 6986A>G polymorphism (CYP3A5*1/*3 alleles) on the pharmacokinetics of everolimus in 28 renal transplant patients and on its in vitro hepatic metabolism using a bank of genotyped human liver microsomes (n=49). We further evaluated in vitro the contribution of CYP3A4, CYP3A5, and CYP2C8 to everolimus hepatic metabolism using recombinant enzymes.
We found no association between CYP3A5 polymorphism and everolimus pharmacokinetics in renal transplant patients. On the other hand, no effect of CYP3A5 polymorphism was observed on the intrinsic clearance of everolimus by human liver microsomes, whereas that of tacrolimus (positive control) was 1.5-fold higher in microsomes carrying the CYP3A5*1 allele than in noncarriers. In vitro data showed that CYP3A4 is a better catalyst of everolimus metabolism than CYP3A5, whereas the opposite was observed for tacrolimus.
This study provides direct and indirect evidence that CYP3A5 genotyping cannot help improve everolimus therapy.
CYP3A5 基因分型可能有助于指导他克莫司和西罗莫司的剂量。本研究旨在评估 CYP3A5 多态性对依维莫司代谢和药代动力学的影响。
我们研究了 CYP3A5 6986A>G 多态性（CYP3A5*1/*3 等位基因）对 28 例肾移植患者依维莫司药代动力学的影响，并使用一组基因分型的人肝微粒体（n=49）研究了其对依维莫司体外肝代谢的影响。我们进一步使用重组酶评估了 CYP3A4、CYP3A5 和 CYP2C8 对依维莫司肝代谢的体外贡献。
我们没有发现 CYP3A5 多态性与肾移植患者依维莫司药代动力学之间存在关联。另一方面，CYP3A5 多态性对人肝微粒体中依维莫司的内在清除率没有影响，而他克莫司（阳性对照）在携带 CYP3A5*1 等位基因的微粒体中比非携带者高 1.5 倍。体外数据表明，CYP3A4 是依维莫司代谢的更好催化剂，而对于他克莫司则相反。
本研究提供了直接和间接的证据，表明 CYP3A5 基因分型不能帮助改善依维莫司治疗。
