Clinical Pharmacy Laboratory, Huashan Hospital, Fudan University, Shanghai, China.
J Clin Pharm Ther. 2011 Oct;36(5):614-24. doi: 10.1111/j.1365-2710.2010.01206.x. Epub 2010 Oct 5.
Tacrolimus (TAC) is metabolized mainly by the CYP3A subfamily and extruded into the intestine by P-glycoprotein, which is encoded by the ABCB1 gene. Several studies have suggested that the CYP3A53 genotype influenced the pharmacokinetics (PK) of TAC. The CYP3A418B and CYP3A53 alleles are clinically important in Chinese subjects because of their relatively high frequency. The present study aimed at evaluating the effects of ABCB1 (C1236T-G2677T/A-C3435T), CYP3A418B and CYP3A5*3 genetic polymorphisms on TAC PK in healthy Chinese subjects.
Data were obtained from a comparative bioavailability study of oral TAC formulations (n = 22). TAC whole blood concentrations were measured by LC-MS/MS. Genetic polymorphisms were determined using a direct sequencing method. Nonlinear mixed-effects modelling (NONMEM) was performed to assess the effect of genotypes and demographics on TAC PKs.
Both CYP3A418B and CYP3A53 polymorphisms affected the TAC PK, whereas ABCB1 genetic polymorphisms and other demographic characteristics did not. The combined genotypes of CYP3A418B and CYP3A53 had a greater impact than either genotype alone, and they were estimated to account for 28·4% of the inter-subject variability of apparent clearance (CL/F) by NONMEM. The CL/F in subjects with CYP3A4*1/1-CYP3A53/3 was 10·3 L/h and was 48·5% in those not carrying CYP3A41/1-CYP3A53/*3.
This is the first study to extensively explore the influence of CYP3A418B, CYP3A53 and ABCB1 genetic polymorphisms on TAC PK in healthy Chinese subjects. The results demonstrated that subjects with a combined genotype of CYP3A4*1/1-CYP3A53/*3 may require lower TAC doses to achieve target concentration levels and further investigation is needed in larger populations to confirm the clinical benefits.
他克莫司（TAC）主要由 CYP3A 亚家族代谢，并由 P-糖蛋白（ABCB1 基因编码）挤出到肠道中。几项研究表明，CYP3A53 基因型影响 TAC 的药代动力学（PK）。由于 CYP3A418B 和 CYP3A53 等位基因在中国人群中相对较高的频率，因此其在临床上很重要。本研究旨在评估 ABCB1（C1236T-G2677T/A-C3435T）、CYP3A418B 和 CYP3A5*3 遗传多态性对健康中国受试者 TAC PK 的影响。
数据来自口服 TAC 制剂的比较生物利用度研究（n=22）。通过 LC-MS/MS 测定全血 TAC 浓度。采用直接测序法确定遗传多态性。采用非线性混合效应模型（NONMEM）评估基因型和人口统计学因素对 TAC PK 的影响。
CYP3A418B 和 CYP3A53 多态性均影响 TAC PK，而 ABCB1 遗传多态性和其他人口统计学特征无影响。CYP3A418B 和 CYP3A53 联合基因型的影响大于单独基因型，NONMEM 估计其占表观清除率（CL/F）个体间变异性的 28.4%。CYP3A4*1/1-CYP3A53/3 受试者的 CL/F 为 10.3 L/h，未携带 CYP3A41/1-CYP3A53/*3 的受试者的 CL/F 为 48.5%。
这是首次广泛探讨 CYP3A418B、CYP3A53 和 ABCB1 遗传多态性对健康中国受试者 TAC PK 的影响的研究。结果表明，CYP3A4*1/1-CYP3A53/*3 联合基因型的受试者可能需要较低的 TAC 剂量以达到目标浓度水平，需要在更大的人群中进一步研究以确认临床获益。
