Department of Clinical Chemistry, Erasmus University Medical Center, Gravendijkwal 230, Rotterdam, The Netherlands.
Pharmacogenomics. 2011 Oct;12(10):1383-96. doi: 10.2217/pgs.11.90. Epub 2011 Sep 8.
CYP3A4 is involved in the oxidative metabolism of many drugs and xenobiotics including the immunosuppressants tacrolimus (Tac) and cyclosporine (CsA). The objective of the study was to assess the potential influence of a new functional SNP in CYP3A4 on the pharmacokinetic parameters assessed by dose requirements and trough blood levels of both calcineurin inhibitors (CNI) in stable renal transplant patients.
PATIENTS & METHODS: A total of 99 stable renal transplant patients receiving either Tac (n = 49) or CsA (n = 50) were genotyped for the CYP3A4 intron 6 C>T (rs35599367) and CYP3A5*3 SNPs. Trough blood levels (Tac or CsA in ng/ml), dose-adjusted Tac or CsA (ng/ml per mg/kg bodyweight) as well as doses (mg/kg bodyweight) required to achieve target concentrations were compared among patients according to allelic status for CYP3A4 and CYP3A5.
Dose-adjusted concentrations were 2.0- and 1.6-fold higher in T-variant allele carriers for the CYP3A4 intron 6 C>T SNP compared with homozygous CC for Tac and CsA, respectively. When CYP3A4/CYP3A5 genotypes were combined, the difference was even more striking as the so-defined CYP3A poor metabolizer group presented dose-adjusted concentration 1.6- and 4.1-fold higher for Tac, and 1.5- and 2.2-fold higher for CsA than the intermediate metabolizer and extensive metabolizer groups, respectively. Multiple linear regression analysis revealed that, taken together, both CYP3A4 intron 6 and CYP3A5*3 SNPs explained more than 60 and 20% of the variability observed in dose-adjusted Tac and CsA, respectively.
The CYP3A4 intron 6 C>T polymorphism is associated with altered Tac and CsA metabolism. CYP3A4 intron 6 C>T along with CYP3A5*3 (especially for Tac) pharmacogenetic testing performed just before transplantation may help identifying patients at risk of CNI overexposure and contribute to limit CNI-related nephrotoxicity by refining the starting dose according to their genotype. Original submitted 5 May 2011; Revision submitted 29 June 2011.
CYP3A4 参与许多药物和外源性物质的氧化代谢，包括免疫抑制剂他克莫司（Tac）和环孢素（CsA）。本研究的目的是评估 CYP3A4 中一种新的功能性 SNP 对稳定肾移植患者两种钙调磷酸酶抑制剂（CNI）的剂量需求和谷浓度的药代动力学参数的潜在影响。
共对 99 例接受他克莫司（n=49）或环孢素（n=50）治疗的稳定肾移植患者进行 CYP3A4 内含子 6 C>T(rs35599367)和 CYP3A5*3SNP 基因分型。根据 CYP3A4 和 CYP3A5 的等位基因状态，比较患者的谷血浓度(Tac或CsA，ng/ml)、剂量调整的Tac或CsA(ng/ml 每 mg/kg 体重)以及达到目标浓度所需的剂量(mg/kg 体重)。
与 Tac 和 CsA 纯合 CC 相比，CYP3A4 内含子 6 C>T 多态性的 T 变体等位基因携带者的剂量调整浓度分别高 2.0 倍和 1.6 倍。当 CYP3A4/CYP3A5 基因型结合时，差异更为明显，因为定义为 CYP3A 弱代谢者的组的 Tac 剂量调整浓度高 1.6-4.1 倍，CsA 高 1.5-2.2 倍，与中间代谢者和广泛代谢者组相比。多元线性回归分析表明，CYP3A4 内含子 6 和 CYP3A5*3SNP 联合解释了 Tac 和 CsA 剂量调整后观察到的变异性的 60%以上和 20%以上。
CYP3A4 内含子 6 C>T 多态性与 Tac 和 CsA 代谢改变有关。CYP3A4 内含子 6 C>T 加上 CYP3A5*3(特别是 Tac)的遗传药理学检测可在移植前进行，有助于识别 CNI 暴露过度的风险患者，并通过根据其基因型调整起始剂量来限制 CNI 相关的肾毒性。
