Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, the Netherlands.
Clin Chem. 2011 Nov;57(11):1574-83. doi: 10.1373/clinchem.2011.165613. Epub 2011 Sep 8.
Tacrolimus (Tac) is a potent immunosuppressant with considerable toxicity. Tac pharmacokinetics varies between individuals and thus complicates its use in preventing rejection after kidney transplantation. This variability might be caused by genetic polymorphisms in metabolizing enzymes.
We used TaqMan analyses to evaluate the impact of a newly discovered CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4) single-nucleotide polymorphism (SNP) (rs35599367C>T; CYP3A4*22) on Tac pharmacokinetics in 185 renal transplant recipients who participated in an international randomized controlled clinical trial (fixed-dose, concentration-controlled study).
The overall mean daily-dose requirement to reach the same predose Tac blood concentration was 33% lower for carriers of the T variant allele than for rs35599367CC patients (95% CI, -46% to -20%; P = 0.018). When combined with the 3 genotype of the CYP3A5 (cytochrome P450, family 3, subfamily A, polypeptide 5) gene, the rs35599367C>T SNP was also associated with a risk of supratherapeutic Tac concentrations (>15 μg/L) during the first 3 days after surgery, with an odds ratio of 8.7 for carriers of the CYP3A4 T allele plus CYP3A53/3 (P = 0.027) and 4.2 for the CYP3A4 CC homozygotes plus CYP3A53/3 (P = 0.002), compared with CYP3A4 CC homozygotes having 1 or 2 CYP3A51 alleles. The overall increase in the Tac dose-adjusted trough blood concentration was +179% for carriers of the CYP3A4 T allele with CYP3A53/3 (P < 0.001), +101% for CYP3A4 CC homozygotes with CYP3A53/3 (P < 0.001), and +64% for CYP3A4 T allele carriers with CYP3A51 (P = 0.020),compared with CYP3A4 CC homozygotes with CYP3A51.
The CYP3A4 rs35599367C>T polymorphism is associated with a significantly altered Tac metabolism and therefore increases the risk of supratherapeutic Tac concentrations early after transplantation. Analysis of this CYP3A4*22 SNP may help in identifying patients at risk of Tac overexposure.
他克莫司（Tac）是一种具有相当毒性的强效免疫抑制剂。Tac 的药代动力学在个体之间存在差异，因此在预防肾移植后排斥反应方面的应用较为复杂。这种可变性可能是由于代谢酶的遗传多态性引起的。
我们使用 TaqMan 分析评估了新发现的 CYP3A4（细胞色素 P450，家族 3，亚家族 A，多肽 4）单核苷酸多态性（SNP）（rs35599367C>T；CYP3A4*22）对 185 名参与国际随机对照临床试验（固定剂量，浓度控制研究）的肾移植受者 Tac 药代动力学的影响。
携带 T 变异等位基因的患者的 Tac 每日平均剂量需求比 rs35599367CC 患者低 33%，可达到相同的预剂量 Tac 血药浓度（95%CI，-46% 至-20%；P=0.018）。当与 CYP3A5（细胞色素 P450，家族 3，亚家族 A，多肽 5）基因的3 基因型结合时，rs35599367C>T SNP 也与术后前 3 天 Tac 浓度高于治疗范围（>15μg/L）的风险相关，携带 CYP3A4 T 等位基因和 CYP3A53/3 的患者比值比为 8.7（P=0.027），携带 CYP3A4 CC 纯合子和 CYP3A53/3 的患者比值比为 4.2（P=0.002），而携带 1 或 2 个 CYP3A51 等位基因的 CYP3A4 CC 纯合子。携带 CYP3A4 T 等位基因和 CYP3A53/3 的患者 Tac 剂量调整后的谷浓度总体增加了 179%（P<0.001），携带 CYP3A4 CC 纯合子和 CYP3A53/3 的患者 Tac 剂量调整后的谷浓度总体增加了 101%（P<0.001），携带 CYP3A4 T 等位基因和 CYP3A51 的患者 Tac 剂量调整后的谷浓度总体增加了 64%（P=0.020），而携带 CYP3A4 CC 纯合子和 CYP3A51 的患者 Tac 剂量调整后的谷浓度总体增加了 64%。
CYP3A4 rs35599367C>T 多态性与 Tac 代谢的显著改变相关，因此增加了移植后早期 Tac 浓度高于治疗范围的风险。对该 CYP3A4*22 SNP 的分析可能有助于识别 Tac 暴露过度的风险患者。
