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目的:探讨CYP3A5不同基因型的肾移植受者应用五酯胶囊对他克莫司谷浓度的影响。方法:回顾性分析2015年6月至2019年10月山东第一医科大学第一附属医院收治的162例首次行肾移植手术患者的病例资料。根据服用他克莫司期间是否联用五酯胶囊将患者分为联用组和未联用组。联用组和未联用组均为81例，男/女比例分别为62/19例和55/26例(n P＝0.219)，年龄分别为(37.21±10.88)岁和(39.26±11.91)岁(n P＝0.103)，体重分别为(66.18±13.89)kg和(62.39±11.64)kg(n P＝0.298)，收缩压分别为(145.00±16.42)mmHg(1 mmHg＝0.133 kPa)和(147.28±20.24)mmHg(n P＝0.276)，舒张压分别为(92.20±12.53)mmHg和(92.25±13.87)mmHg(n P＝0.886)，天冬氨酸转氨酶分别为(17.06±13.11)U/L和(12.24±8.59)U/L(n P＝0.015)，丙氨酸转氨酶分别为(16.57±8.37)U/L和(17.76±9.12)U/L(n P＝0.463)，空腹血糖分别为(7.18±2.74)mmol/L和(8.70±3.48)mmol/L(n P＝0.006)，血红蛋白分别为(101.05±18.67)g/L和(98.96±17.53)g/L(n P＝0.789)，肾移植术前肌酐分别为(797.32±279.82)μmol/L和(665.22±296.55)μmol/L(n P＝0.007)，术前估计肾小球滤过率分别为(8.85±3.71)ml/(min·1.73mn 2)和(11.47±14.11)ml/(min·1.73mn 2)(n P＝0.130)。本研究162例中，CYP3A5*1*3基因型86例(53.09%)，CYP3A5*1*1基因型17例(10.49%)，CYP3A5*3*3基因型59例(36.42%)，CYP3A5*1的最小等位基因频率为37.04%。联用组中，CYP3A5*1*3基因型47例(58.02%)，CYP3A5*1*1基因型12例(14.81%)，CYP3A5*3*3基因型22例(27.16%)；未联用组中，CYP3A5*1*3基因型39例(48.15%)，CYP3A5*1*1基因型5例(6.17%)，CYP3A5*3*3基因型37例(45.68%)，两组的基因型差异有统计学意义(n P＝0.024)。本研究162例均服用以他克莫司[首次剂量：0.15~0.30 mg/(kg·d)]为基础的三联免疫抑制方案(他克莫司+吗替麦考酚酯+糖皮质激素)，联用组加用五酯胶囊(11.25 mg，2次/日)。采用酶联免疫法测定他克莫司谷浓度，比较两组间他克莫司谷浓度的差异，分析他克莫司谷浓度与CYP3A5基因型的相关性；比较联用组各基因型患者应用五酯胶囊前后的他克莫司谷浓度差异。采用多重线性回归分析影响他克莫司谷浓度的因素。n 结果:联用组的他克莫司剂量校正谷浓度(Cn 0/D)高于未联用组，增高幅度与基因型相关。联用组和未联用组CYP3A5*3*3基因型患者的他克莫司Cn 0/D分别为(12.15±2.95)(ng·mln -1/0.1mg·kgn -1·dn -1)和(9.99±2.33)(ng·mln -1/0.1mg·kgn -1·dn -1)(n P＝0.004)，CYP3A5*1*3基因型患者分别为(11.11±3.20)(ng·mln -1/0.1mg·kgn -1·dn -1)和(6.86±1.62)(ng·mln -1/0.1mg·kgn -1·dn -1)(n P<0.001)，差异均有统计学意义；CYP3A5*1*1基因型患者分别为(8.29±2.64)(ng·mln -1/0.1mg·kgn -1·dn -1)和(6.16±2.87)(ng·mln -1/0.1mg·kgn -1·dn -1)，差异无统计学意义(n P＝0.160)。联用组各基因型患者应用五酯胶囊前后的他克莫司Cn 0/D分别为CYP3A5*3*3基因型(7.18±2.33)(ng·mln -1/0.1mg·kgn -1·dn -1)和(13.33±3.09)(ng·mln -1/0.1mg·kgn -1·dn -1)(n P<0.001)，CYP3A5*1*3基因型(5.14±2.14)(ng·mln -1/0.1mg·kgn -1·dn -1)和(10.61±3.20)(ng·mln -1/0.1mg·kgn -1·dn -1)(n P<0.001)，CYP3A5*1*1基因型(5.17±3.75)(ng·mln -1/0.1mg·kgn -1·dn -1)和(8.31±2.74)(ng·mln -1/0.1mg·kgn -1·dn -1)(n P＝0.002)，差异均有统计学意义。多重线性回归分析结果显示，联用五酯胶囊(β＝0.508，n P<0.001)和基因型(CYP3A5*1*3与CYP3A5*3*3：β＝-0.361，n P<0.001；CYP3A5*1*1与CYP3A5*3*3：β＝-0.425，n P<0.001)是影响他克莫司Cn 0/D的因素，而肾移植受者的性别(β＝-0.100，n P＝0.124)和年龄(β＝-0.003，n P＝0.967)对他克莫司Cn 0/D无影响。n 结论:患者的CYP3A5基因型和联用五酯胶囊是肾移植术后影响他克莫司Cn 0/D的主要因素，为尽快达到预期的谷浓度，应考虑肾移植受者的CYP3A5基因与合并用药之间的交互作用。n “,”Objective:To study the effect of Wuzhi capsules on tacrolimus trough concentration in kidney transplant recipients with different CYP3A5 genotypes.Methods:From June 2015 to October 2019, 162 patients who underwent renal transplantation for the first time were retrospectively analyzed. The patients were divided into two groups, combined and uncombined, according to whether combined with Wuzhi capsules. There were 81 cases in the uncombined group (55 males and 26 females), and 81 in the combined group (62 males and 19 females). There was no significant difference between the two groups(n P=0.219). The ages of the uncombined group and the combined group were (39.26±11.91) years old and (37.21±10.88) years old (n P=0.103), the weights were (62.39±11.64) kg and (66.18±13.89)kg (n P=0.298), systolic blood pressure were (147.28±20.24) mmHg and (145.00±16.42) mmHg (1 mmHg=0.133 kPa)(n P=0.276), diastolic blood pressure were (92.25±13.87) mmHg and (92.20±12.53) mmHg (n P=0.886), alanine aminotransferase were (12.24±8.59) U/L and (17.06±13.11) U/L (n P=0.015), aspartate aminotransferase were (17.76±9.12) U/L and (16.57±8.37) U/L (n P=0.463), fasting blood glucose were (8.70±3.48) mmol/L and (7.18±2.74)mmol/L (n P=0.006), hemoglobin were (98.96±17.53) g/L and (101.05±18.67) g/L (n P=0.789), creatinine were (665.22±296.55) μmol/L and (797.32±279.32) μmol/L ( n P=0.007), estimated glomerular filtration rate were (11.47±14.11) ml/(min·1.73mn 2) and (8.85±3.71) ml/(min·1.73mn 2) (n P=0.130)in the kidney transplant recipients before surgery. Among the 162 cases in this study, there were 86 cases (53.09%) of CYP3A5*1*3 genotype, 17 cases (10.49%) of CYP3A5*1*1 genotype, 59 cases (36.42%) of CYP3A5*3*3 genotype, and the minimum allele frequency of CYP3A5*1 was 37.04%. In the uncombined group, CYP3A5*1*3 genotype 39 cases (48.15%), CYP3A5*1*1 genotype 5 cases (6.17%), and CYP3A5*3*3 genotype 37 cases (45.68%). In the combined group, CYP3A5*1*3 genotype 47 cases (58.02%), CYP3A5*1*1 genotype 12 cases (14.81%), and CYP3A5*3*3 genotype 22 cases (27.16%), with statistically significant differences in the two groups (n P=0.024). The patients were treated with a triple immunosuppressive regimen (tacrolimus+ mycophenolate mofetil+ glucocorticoid) based on tacrolimus [initial dose: 0.15-0.30 mg/(kg·d)], combination of Wuzhi capsules in the combination group (11.25 mg, twice a day). The trough concentration of tacrolimus was detected by enzyme-linked immunosorbent assay, compare the difference in the trough concentration of tacrolimus between the two groups. The relationship between the effect of Wuzhi capsules and CYP3A5 gene polymorphism was compared, and compare the changes before and after the application of CYP3A5 genotype combined with Wuzhi Capsules. The influencing factors of tacrolimus trough concentration were analyzed by multiple linear regression.n Results:In the combined with Wuzhi capsules, the dose corrected trough concentration (Cn 0/D) of tacrolimus was higher than that in patients without Wuzhi capsules, and the extent of increase was related to genotype. The Cn 0/D of tacrolimus in patients with CYP3A5*3*3 genotype in the combination and non-combination groups were (12.15±2.95) (ng·mln -1/0.1mg·kgn -1·dn -1) and (9.99±2.33) (ng·mln -1/0.1mg·kgn -1·dn -1) (n P=0.004), CYP3A5*1*3 genotype were (11.11±3.20) (ng·mln -1/0.1mg·kgn -1·dn -1) and (6.86±1.62) (ng·mln -1/0.1mg·kgn -1·dn -1) (n P<0.001), and there were significant difference. However, CYP3A5*1*1 genotype were(8.29±2.64) (ng·mln -1/0.1mg·kgn -1·dn -1) and (6.16±2.87) (ng·mln -1/0.1mg·kgn -1·dn -1) (n P=0.160), there was no significant difference. The tacrolimus Cn 0/D of the combined group before and after the Wuzhi capsule were as follows: CYP3A5*3*3 genotype: (7.18±2.33)(ng·mln -1/0.1mg·kgn -1·dn -1) and (13.33±3.09) (ng·mln -1/0.1mg·kgn -1·dn -1) (n P<0.001); CYP3A5*1*3 genotype: (5.14±2.14) (ng·mln -1/0.1mg·kgn -1·dn -1) and (10.61±3.20) (ng·mln -1/0.1mg·kgn -1·dn -1) (n P<0.001); CYP3A5*1*1 genotype: (5.17±3.75) (ng·mln -1/0.1mg·kgn -1·dn -1) and (8.31±2.74) (ng·mln -1/0.1mg·kgn -1·dn -1)(n P=0.002), and the differences were statistically significant. The results of multiple linear regression showed that the combination of Wuzhi capsules (β=0.508,n P<0.001) and CYP3A5 genotype(CYP3A5*1*3 and CYP3A5*3*3: β=-0.361,n P<0.001; CYP3A5*1*1 and CYP3A5*3*3: β=-0.425,n P<0.001)could influence the trough concentration. The sex (β=-0.100,n P=0.124) and age (β=-0.003,n P=0.967) of renal transplant recipients had no statistical significance to tacrolimus Cn 0/D.n Conclusions:In the renal transplant patients, CYP3A5 genotype and combined use of Wuzhi capsules are the main factors affecting tacrolimus Cn 0/D. In order to achieve the expected trough concentration as soon as possible, the interaction between CYP3A5 genotypes and drug combination should be considered.n