Chakkera H A, Chang Y-H, Bodner J K, Behmen S, Heilman R L, Reddy K S, Mulligan D C, Moss A A, Khamash H, Katariya N, Hewitt W R, Pitta T L, Frassetto L A
Division of Nephrology, Mayo Clinic, Phoenix, Arizona 85054, USA.
Transplant Proc. 2013 Jan-Feb;45(1):137-41. doi: 10.1016/j.transproceed.2012.10.023.
Tacrolimus pharmacokinetics vary due to single nucleotide polymorphisms (SNPs) in metabolizing enzymes and membrane transporters that alter drug elimination. Clinically we observed that Native Americans require lower dosages of tacrolimus to attain trough levels similar to Caucasians. We previously demonstrated that Native Americans have decreased oral clearance of tacrolimus, suggesting that Native Americans may have more variant SNPs and, therefore, altered tacrolimus pharmacokinetic parameters. We conducted 12-hour pharmacokinetic studies on 24 adult Native American kidney transplant recipients on stable doses of tacrolimus for at least 1 month posttransplantation. Twenty-four Caucasian kidney transplant recipients were compared as controls. SNPs encoding the genes for the enzymes (CYP3A4, CYP3A5) and transporters (ABCB1, BCRP, and MRP1) were typed using TaqMan. The mean daily tacrolimus dose in the Native Americans was 0.03 ± 0.02 compared with the Caucasians 0.5 ± 0.3 (mg/kg/d; P = .002), with no significant differences in trough levels, (6.7 ± 3.1 vs 7.4 ± 2.1 ng/dL; P = .4). Many Native Americans, but not Caucasians, demonstrated the 3/*3 - C3435T CC and the *3/*3 -G2677T GG genotype combination previously associated with low tacrolimus dosing. Native Americans required significantly lower tacrolimus doses than Caucasians to achieve similar tacrolimus trough levels, in part due to lower tacrolimus clearance from decreased drug metabolism and excretion.
由于代谢酶和膜转运蛋白中的单核苷酸多态性（SNP）会改变药物消除，他克莫司的药代动力学存在差异。临床上我们观察到，美国原住民达到与白种人相似的谷浓度所需的他克莫司剂量较低。我们之前证明，美国原住民他克莫司的口服清除率降低，这表明美国原住民可能有更多的变异SNP，因此他克莫司的药代动力学参数发生改变。我们对24名成年美国原住民肾移植受者进行了12小时药代动力学研究，这些受者在移植后至少1个月内接受稳定剂量的他克莫司治疗。将24名白种人肾移植受者作为对照进行比较。使用TaqMan对编码酶（CYP3A4、CYP3A5）和转运蛋白（ABCB1、BCRP和MRP1）的基因的SNP进行分型。美国原住民的他克莫司平均日剂量为0.03±0.02，而白种人为0.5±0.3（mg/kg/天；P = 0.002），谷浓度无显著差异（6.7±3.1对7.4±2.1 ng/dL；P = 0.4）。许多美国原住民（而非白种人）表现出先前与低剂量他克莫司相关的3/3 - C3435T CC和3/*3 - G2677T GG基因型组合。美国原住民达到相似的他克莫司谷浓度所需的他克莫司剂量显著低于白种人，部分原因是药物代谢和排泄减少导致他克莫司清除率降低。
