Deininger Kimberly M, Vu Anh, Page Robert L, Ambardekar Amrut V, Lindenfeld JoAnn, Aquilante Christina L
Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA.
Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA.
Clin Transplant. 2016 Sep;30(9):1074-81. doi: 10.1111/ctr.12790. Epub 2016 Jul 11.
Cytochrome P450 (CYP) 3A polymorphisms are associated with variable CYP3A metabolizing enzyme activity and tacrolimus pharmacokinetics. We sought to determine the singular and combined impact of CYP3A422 and CYP3A53 variants on tacrolimus drug disposition in adult heart transplant recipients.
The retrospective study included 76 patients greater than one year post-heart transplant and receiving tacrolimus. Patients were genotyped for CYP3A422 and CYP3A53, and combined genotypes were classified as follows: extensive metabolizers (EM, CYP3A41/1+CYP3A51 carriers), intermediate metabolizers (IM, CYP3A41/1+CYP3A53/3, or CYP3A422 carriers+CYP3A51 carriers), and poor metabolizers (PM, CYP3A422 carriers+CYP3A5*3/*3). The primary outcome was tacrolimus dose-adjusted trough concentration (C0 /D, ng/mL per mg/d).
In singular analysis, tacrolimus C0 /D did not differ significantly between CYP3A4*22 genotype groups. However, tacrolimus C0 /D was 1.8-fold lower (P<.001) in CYP3A5 expressers vs non-expressers. When combined CYP3A genotypes were evaluated, tacrolimus C0 /D was 1.8-fold lower in EMs vs IMs (P<.001) and EMs vs PMs (P=.001). Tacrolimus C0 /D did not differ significantly between CYP3A IMs vs PMs.
Combined CYP3A genotype was associated with tacrolimus drug disposition in adult heart transplant recipients, but the effect was largely driven by CYP3A53. These data suggest that CYP3A422 and combined CYP3A genotypes are unlikely to provide additional information beyond CYP3A5 genotype.
细胞色素P450（CYP）3A基因多态性与CYP3A代谢酶活性的变化以及他克莫司的药代动力学相关。我们试图确定CYP3A422和CYP3A53变异对成年心脏移植受者他克莫司药物处置的单一和联合影响。
这项回顾性研究纳入了76例心脏移植术后一年以上且接受他克莫司治疗的患者。对患者进行CYP3A422和CYP3A53基因分型，联合基因型分类如下：广泛代谢者（EM，CYP3A41/1 + CYP3A51携带者）、中间代谢者（IM，CYP3A41/1 + CYP3A53/3，或CYP3A422携带者 + CYP3A51携带者）和慢代谢者（PM，CYP3A422携带者 + CYP3A5*3/*3）。主要结局是他克莫司剂量调整后的谷浓度（C0 /D，每mg/d的ng/mL）。
在单因素分析中，CYP3A4*22基因型组之间他克莫司C0 /D无显著差异。然而，CYP3A5表达者与非表达者相比，他克莫司C0 /D低1.8倍（P <.001）。评估联合CYP3A基因型时，EM组与IM组相比他克莫司C0 /D低1.8倍（P <.001），EM组与PM组相比也低1.8倍（P =.001）。CYP3A的IM组与PM组之间他克莫司C0 /D无显著差异。
联合CYP3A基因型与成年心脏移植受者他克莫司药物处置相关，但这种影响主要由CYP3A53驱动。这些数据表明，CYP3A422和联合CYP3A基因型不太可能提供超出CYP3A5基因型的额外信息。
