CYP3A4*18B和CYP3A5*3基因多态性对肾移植患者他克莫司剂量及浓度的影响

研究CYP3A5*3和CYP3A4*18B基因突变对他克莫司血药浓度/剂量×体表面积(C/D′)、不良反应和急性排斥反应的影响。采用聚合酶链反应(PCR)和限制性内切片段长度多态性(RFLP)方法检测227例肾移植患者CYP3A5*3和CYP3A4*18B基因型,比较不同基因型患者之间他克莫司的C/D′值、不良反应和急性排斥反应发生率的差异。测得CYP3A4*18B和CYP3A5*3基因型在肾移植患者中的突变频率分别为30.8%和74.2%。消除CYP3A5*3等位基因影响后,CYP3A4*18B各基因型间他克莫司C/D′值无显著性差异(P>0.05);而消除CYP3A4*18B等位基因影响后,CYP3A5*1/*1和*1/*3基因型患者的他克莫司C/D′值显著低于*3/*3(P<0.01)。CYP3A4*18B和CYP3A5*3基因多态性与不良反应和排斥反应间差异无统计学意义(P>0.05)。     

CYP3A4和CYP3A5基因多态性对汉族肾移植患者他克莫司血药浓度的影响

目的:研究CYP3A4* 18B (rs2242480)、CYP3 A5 6989 A/G(rs776746)两个位点的基因多态性对肾移植术后他克莫司血药浓度/校正剂量比值(C/D)的影响,对肾移植患者基因导向的他克莫司个体化给药提供有意义的信息和数据.方法:101名健康志愿者和56例亲体肾移植且随访超过6个月的患者参加本研究,应用基因芯片法检测2个位点的基因型.用均相酶扩大免疫分析法(EMIT)测定术后7d、14 d、1个月、3个月和6个月时血药浓度.比较不同基因型间他克莫司C/D值之间的差异.结果:在101例汉族人群中,CYP3A4、CYP3A5的等位基因频率分别为:23.75％、73.80％.移植术后6个月内,CYP3A5 GG型(*3/*3)的C/D值显著高于AA型(*1/*1)和AG型(*1/*3)(P＜0.05).CYP3A5 AA型与AG型相比较,差异无统计学意义(P＞0.05).CYP3A4 CC型(*1/*1)的C/D值显著高于CT型(*1/*18B)和TT型(*18B/* 18B)(P＜0.05),其中CT型与TT型比较,C/D值差异无统计学意义(P＞0.05) 结论:肾移植患者术后服用他克莫司C/D值与CYP3A4、CYP3A5基因多态性具有显著相关性.     

肾移植患者他克莫司的血药浓度与CYP3A5*3基因多态性的关系

目的研究CYP3A5*3基因突变对他克莫司全血谷浓度(经体表面积剂量校正)、不良反应和急性排斥反应的影响。方法采用聚合酶链反应(PCR)和限制性内切片段长度多态性(RFLP)方法检测227例肾移植患者CYP3A5*3基因型,比较不同基因型患者之间他克莫司的全血谷浓度、不良反应和急性排斥反应发生率的差异。结果 CYP3A5*3基因多态性中,*1/*1型18例(7.9%),*1/*3型81例(35.7%),*3/*3型128例(56.4%)。肾移植术后3个月内,*1/*1型、*1/*3型和*3/*3型患者的他克莫司全血谷浓度经体表面积剂量校正后分别为1.84±0.71、2.06±0.83和4.11±2.13,*1/*1型和*1/*3型之间差异未见统计学意义(P>0.05),但与*3/*3型之间差异均有高度统计学意义(P<0.01)。组间不良反应和急性排斥反应发生率之间差异无统计学意义(P>0.05)。结论肾移植患者的CYP3A5*3基因多态性与他克莫司的服用剂量密切相关,对含CYP3A5*3等位基因的患者在应用他克莫司时应较常规减少用药剂量并注意不良反应的发生,而对CYP3A5野生型的肾移植患者应适当增加服药次数以降低排异反应。     

CYP3A4、CYP3A5和CYP3A7的基因多态性对中国汉族肾移植患者他克莫司药动学的影响

摘 要 目的：探讨中国汉族肾移植患者中,CYP3A5*3（rs776746）、CYP3A4*1G(rs2242480)、CYP3A4 rs4646437、CYP3A7 rs2257401及CYP3A7 rs10211单核苷酸多态性对免疫抑制药他克莫司（TAC）药动学的影响。方法：采用直接测序法,对85例肾移植的患者进行基因分型。采用酶放大免疫分析法测定患者TAC的谷浓度（C0）。比较不同基因型患者间TAC浓度剂量比值的差异。结果：在85例肾移植患者中,CYP3A5*3 A、CYP3A4*1G T、CYP3A4 rs4646437 T、CYP3A7 rs2257401C及CYP3A7 rs10211 G等位基因的频率分别为29.4%,27.6%,13.5%,26.5%及27.6%。肾移植术后1个月时,CYP3A5*3、CYP3A7 rs2257401及CYP3A7 rs10211影响TAC的谷浓度（P<0.01）。CYP3A5*3 A、CYP3A7 rs2257401 C及CYP3A7 rs10211 G等位基因携带者,TAC剂量校正浓度分别比其相应非携带者剂量校正浓度低约50%左右。而本研究未发现CYP3A4*1G和CYP3A4 rs4646437基因多态性与TAC校正谷浓度相关（P>0.05）。结论：在中国汉族肾移植患者中,CYP3A5*3、CYP3A7 rs2257401及CYP3A7 rs10211的单核苷酸多态性与移植术后1个月内TAC的药代动力学有相关性,但把这种相关性应用在临床上,以优化他克莫司的剂量,尚待进一步的研究。     

CYP3A4、3A5基因多态性对肾移植患者术后他克莫司浓度/剂量比值的影响

摘 要 目的:探讨CYP3A4*18B(82266G>A,rs2242480)、CYP3A5*3(6986A>G,rs776746)位点的基因多态性对肾移植术后服用他克莫司（FK506）用药的指导作用。方法: 采用PCR RFLP(聚合酶链反应 限制性片段长度多态性)方法对280名肾移植患者进行CYP3A4*18B、CYP3A5*3基因型检测,利用化学发光微粒子免疫分析技术（CMIA）检测肾移植患者FK506血浓度,比较不同基因型患者之间FK506血药谷浓度/剂量*体质量(C₀/D)比值。 结果:280例肾移植患者中,CYP3A4*18B和CYP3A5*3基因型的突变频率分别为29.1%和69.3%。CYP3A4*18B/*18B基因型肾移植患者术后1个月,3个月FK506的C₀及C₀/D值显著低于CYP3A4*1/*1、CYP3A4*1/*18B基因型（P<0.05）。CYP3A5*3/*3基因型肾移植患者术后7日,1个月FK506的C₀及C₀/D值显著高于CYP3A5*1/*1、CYP3A5*1/*3基因型（P<0.05）。将CYP3A4*18B和CYP3A5*3进行单倍体基因型组合分析,用药后15 d、1个月,GG-GG基因型组的C₀明显高于AA-GG基因型组（P<0.05）;用药后6月,GG-GG、GA-GG、GA-AG基因型组的C₀均明显高于AA GG基因型组（P<0.05）。结论: CYP3A4*18B和CYP3A5*3基因多态性对肾移植患者的FK506血药浓度及其C₀/D值有一定影响,患者在使用FK506前进行CYP3A4*18B和CYP3A5*3基因型检测,对预测FK506用药剂量有一定的指导作用。     

CYP3A5/3A4多态性对肾移植患者术后早期他克莫司剂量的影响

目的：探索肾移植患者术后早期遗传因素与他克莫司（ FK506）个体化给药的规律,并探讨各单倍型患者在术后不同时间所需剂量的个体差异。方法：观察113例肾移植术后常规应用他克莫司+霉酚酸酯+泼尼松三联免疫抑制治疗的患者,记录术后早期（3、5、7和14 d）FK506全血谷浓度（ C0）和剂量（ D,每日每 kg 体重剂量）,测定每个患者CYP3A5及 CYP3A4基因多态性。采用酶联免疫吸附法（ELISA）监测患者术后 FK506的 C0,DNA 直接测序法测定患者CYP3A5*3、CYP3A4*18B 基因多态性。在此基础上,根据患者基因型进行分组,比较不同基因型患者 FK506的 C0、D 及C0／ D。结果：113例肾移植患者 CYP3A5*3和 CYP3A4*18B 突变等位基因发生的频率分别为73.0%和30.5%,各基因频率达到遗传平衡。CYP3A5不表达组（CYP3A5*3／*3）的 C0／ D 是 CYP3A5表达组（CYP3A5*1）的2.1~2.5倍（P ﹤0.05）;CYP3A4不表达组（CYP3A4*1／*1）的 C0／ D 是 CYP3A4表达组（CYP3A4*18B）的1.3~1.7倍（P ﹤0.05）;对于CYP3A5- CYP3A4单倍型,GG - GG 组的 C0／ D 是 AA - AA 组的2.0~2.8倍（P ﹤0.05）。各基因型患者达目标靶浓度的人数比例随术后时间延长逐步增加,而 AA - AA 组达靶浓度人数比例始终最少（ P ﹤0.05）。结论：CYP3A5*3和CYP3A4*18B基因多态性对肾移植术后 FK506的药动学有显著影响,肾移植术前可通过对患者单独进行 CYP3A5基因型的测定来确定术后早期 FK506初始剂量,从而实现个体化用药。     

肾移植受者CYP3A5基因多态性对他可莫司代谢的影响

目的研究CYP3A基因多态性对肾移植受者他可莫司代谢的影响。方法50例肾移植受者采用FK506＋霉酚酸酯＋强的松三联免疫抑制方案,FK506起始剂量0．15mg／（kg·d）,1w后根据目标血药浓度调整。CYP3A5基因多态性检测采用聚合酶链反应-限制性片段长度多态性（PCR—RFLP）方法,50例肾移植受者分为＊1／＊1型（12例）、＊1／＊3型（16例）、＊3／＊3型（22例）共3组。比较6个月内FK506的血药浓度／剂量比。结果 肾移植术后7天、1月、3月、6月＊3／＊3型患者FK506的血药浓度／剂量比显著高于＊1／＊1型和＊1／＊3型（P〈0．05）。结论由于CYP3A5基因多态性影响,＊1／＊1型组的患者早期难以达到有效FK506目标血药浓度,应该提高该组患者的起始用药剂量,根据CYP3A5基因多态性作为FK506个体化用药的依据,可以减少早期急性排斥反应,提高肾移植的临床效果。     

CYP3A5*3基因多态性对稳定期肾移植受者他克莫司血药浓度及肾功能的影响

目的:探讨细胞色素P_(450)(CYP)3A5*3(rs776746)基因多态性对稳定期肾移植受者他克莫司(TAC)血药浓度和肾功能的影响。方法:选择1995年3月-2014年12月于我院行肾移植术并于术后接受以TAC为基础的三联抗排斥方案(TAC+麦考酚钠+醋酸泼尼松)治疗且行定期门诊随访的稳定期肾移植受者98例,收集其2016年1-12月的随访信息。采用化学发光微粒子免疫分析法检测肾移植受者的TAC血药谷浓度,并计算经体质量和日剂量校正的标准化血药浓度(C/D)值;采用干化学法检测血肌酐(Scr)水平;采用聚合酶链反应-限制性片段长度多态性法、直接测序法检测CYP3A5*3基因分型。采用Kruskal Wallis H检验或Mann-Whitney U检验分析CYP3A5*3基因多态性与TAC的C/D值、Scr水平的相关性。结果:98例肾移植受者中,CYP3A5*3*1/*1(AA)、*1/*3(AG)、*3/*3(GG)型分别有9、37、52例,各基因型频率分别为9.18%、37.76%、53.06%,均符合Hardy-Weinberg遗传平衡(P>0.05)。不同基因型受者TAC血药谷浓度比较,差异无统计学意义(P>0.05);TAC剂量和C/D值比较,差异均有统计学意义(P<0.05)。其中,CYP3A5*3*3/*3型受者TAC剂量显著低于*1/*3、*1/*1型受者,且*1/*3型受者显著低于*1/*1型受者;*3/*3型受者TAC的C/D值显著高于*1/*3、*1/*1型受者,且*1/*3型受者显著高于*1/*1型受者,差异均有统计学意义(P<0.05)。不同基因型受者Scr水平比较,差异无统计学意义(P>0.05)。结论:CYP3A5*3基因多态性对我国稳定期肾移植受者TAC的血药浓度有显著影响,*3等位基因携带者TAC的C/D值更高,且每日所需的TAC剂量更低;但CYP3A5*3基因多态性可能与其Scr水平无关。     

CYP3A5、ABCB1基因多态性对中国肾移植患者服用他克莫司剂量和血药浓度的影响

目的：研究肾移植患者CYP3A5、ABCB1基因多态性对肾移植术后患者他克莫司（TAC）血药浓度及给药剂量的影响。方法：采集83例中国肾移植患者术后3个月内TAC的常规监测的谷浓度（C0）。测定受试者CYP3A5*3（rs776746）、ABCB1 1236C＞ T（rs1128503）、2677G＞ T/A（rs2032582）、3435C＞ T（rs1045642）位点的基因型,分析基因多态性对TAC的C0、剂量的影响。结果：患者CYP3A5、ABCB1基因型频率均符合Hardy-Weinberg平衡（P ＞ 0.05）。在移植后3个月期间,CYP3A5*3/*3型患者相较于携带*1等位基因患者,具有更高的C0和更低的剂量（P ＜ 0.05）。ABCB1 2677GG基因型的C0显著低于GT、GA、AA、TT、AT型（P ＜ 0.05）;3435CT型的C0显著高于CC、TT型（P ＜ 0.05）。根据ABCB1的单倍型进行分组,并与CYP3A5进行了联合分析,结果发现,发现CYP3A5*1/*1与*1/*3组与*3/*3组中,不同ABCB1单倍型对TAC血药浓度影响的差异无统计学意义。术后随时间延长,CYP3A5*3/*3型患者的TAC剂量逐步降低,而携带*1基因患者的剂量则呈增加趋势。结论：CYP3A5比ABCB1基因多态性对肾移植受者TAC血药浓度的影响更显著,若达到相同的血药浓度,CYP3A5*3/*3型患者每日所服用的剂量更低。根据CYP3A5基因型制定给药方案,有助于尽早达到浓度标准,达到精准治疗的目标。     

基因多态性对肾移植术后他克莫司药动学影响的研究进展

肾移植是终末期肾脏疾病有效的治疗手段,为降低肾移植术后排斥反应风险,患者术后需长期服用免疫抑制剂,他克莫司为目前最广泛应用的钙调蛋白类免疫抑制剂.然而,在临床应用中,他克莫司表现出治疗窗窄、药动学个体差异大等特点.在影响其个体间差异的相关因素中,基因多态性是目前研究的热点之一.本文通过检索文献,就常见的基因多态性对他克...     

Lack of tacrolimus circadian pharmacokinetics and CYP3A5 pharmacogenetics in the early and maintenance stages in Japanese renal transplant recipients

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Circadian variations of tacrolimus pharmacokinetics are controversial.
• Also, the pharmacokinetics has time-dependent variability, such as a decrease in oral clearance and increase in the dose-adjusted AUC after transplantation.
• Although the CYP3A5 polymorphism is associated with tacrolimus pharmacokinetics, differences in the influence of this gene on the pharmacokinetics between the early and maintenance stages have not yet been clarified.

WHAT THIS STUDY ADDS

• Tacrolimus pharmacokinetics did not show circadian variation in either the early or maintenance stage with our designated-time administration strategy.
• Based on previous results and our own findings, the interval between food consumption and tacrolimus administration might influence the interindividual and interinstitutional variability of tacrolimus chronopharmacokinetics.
• The CYP3A5 polymorphism may be associated with the time-dependent changes in tacrolimus oral clearance.

AIMS

We investigated whether tacrolimus pharmacokinetics shows circadian variation and the influence of the CYP3A5 A6986G polymorphism on the pharmacokinetics in both the early and maintenance stages after renal transplantation.

METHODS

Tacrolimus was administered twice daily at specified times (09.00 and 21.00 h) throughout the pre- and post-transplant period according to the trough-targeting strategy. Fifty recipients with stable graft function were studied on day 28 and beyond 1-year post transplantation. Whole blood samples were collected prior to and 1, 2, 3, 4, 6, 9 and 12 h after both the morning and evening doses during hospitalization.

RESULTS

Tacrolimus pharmacokinetics did not show circadian variation in either the early or maintenance stage [AUC_0–12 197.1 (95% confidence interval 182.9, 212.3) in daytime vs. 203.6 ng h ml⁻¹ (189.8, 217.4) in the night-time at day 28, 102.0 (92.1, 111.9) vs. 107.7 (97.9, 117.5) at 1 year, respectively]. In CYP3A5 *1 allele carriers (CYP3A5 expressers), body weight-adjusted oral clearance was markedly decreased from the early stage to the maintenance stage [0.622 (0.534, 0.709) to 0.369 l h⁻¹ kg⁻¹ (0.314, 0425)] compared with a smaller decrease [0.368 (0.305, 0.430) to 0.305 (0.217, 0.393)] in CYP3A5 non-expressers; however, the CYP3A5 genetic variation did not influence tacrolimus chronopharmacokinetics.

CONCLUSION

Equivalent daytime and night-time tacrolimus pharmacokinetics were achieved during both the early and maintenance stages with our specified-time administration strategy. The CYP3A5 polymorphism may be associated with the time-dependent changes in the oral clearance of tacrolimus, suggesting that genotyping of this polymorphism is useful for determining the appropriate dose of tacrolimus in both the early and maintenance stages after renal transplantation.     

Influence of CYP3A5 genetic polymorphism on cyclosporine A metabolism and elimination in Chinese renal transplant recipients

AIM: To investigate whether the CYP3A5*3 polymorphism would affect cyclosporine A (CsA) metabolism in Chinese renal transplant patients. METHODS: The CYP3A5*3 genotype was determined in Chinese renal transplant recipients using polymerase chain reaction and amplification of specific alleles (PCR-ASA). The concentrations of CsA and metabolites were separately measured by fluorescence polarization immunoassay and dose-adjusted trough concentrations and metabolic ratio (MR) values were calculated. RESULTS: The trough concentrations adjusted with the dose was significantly higher in the wild allele carriers compared to both the homozygous (*3*3) and heterozygous variants (*1*3). However, no significant difference was found for the dose-adjusted metabolite concentrations. The MR values for the 3 genotype groups were as follows: 0.92+/-0.62 for CYP3A5*3/ *3 (n=14), 0.99+/-0.51 for CYP3A5*1/*3 (n=15), and 1.45+/-0.62 for CYP3A5*1/*1 (n=9), respectively. Post hoc comparisons showed that only the MR values between the CYP3A5*3/*3 group and the CYP3A5*1/*1 group were significantly different. CONCLUSION: The CYP3A5*3 polymorphism exerted little effect on cyclosporine metabolism. The MR may be a more accurate indicator for therapeutic drug monitoring, considering its integrated information on body exposure of both parent drugs and metabolites.     

CYP3A5和MDR1基因多态性对中国肝移植患者他克莫司药动学的影响

目的探讨细胞色素P450酶3A5（CYP3A5）基因和多药耐药基因（MDR1）C1236T、G2677T／A、C3435T多态性对肝移植患者口服他克莫司（TAC）后体内药动学参数的影响。方法采集28例肝移植患者手术后第1周和第3周血标本,采用LC—MS／MS法检测TAC血药浓度,计算主要药动学参数。采用聚合酶链反应结合基因测序分析28例肝移植患者CYP3A5＊3和MDR1主要基因型。结果携带MDR1 3435T基因型的肝移植患者口服TAC后,药动学参数AUC0→1和ρmax明显高于3435CC型患者,而CYP3A5＊3、MDR1 C1236T和G2677T／A基因多态性对TAC的药动学参数无明显影响。结论携带MDR1 3435T基因型肝移植患者比3435CC型患者需要较高剂量才能达到目标浓度。     

CYP3A5和POR基因多态性对肾移植患者住院期间他克莫司浓度剂量的影响

目的：研究CYP3A5和POR基因多态性对肾移植患者住院期间他克莫司（FK506）浓度（C）、剂量（D）以及浓度剂量比（C/D）的影响。方法：以290例肾移植患者为研究对象,使用聚合酶链式反应（PCR）-限制性内切片段长度多态性（RFLP）法和测序法检测患者CYP3A5*3 A>G（rs776746）和POR*28 C>T（rs1057868）基因型,比较肾移植术后28 d内不同基因型患者之间FK506的C、D以及C/D的差异。结果：CYP3A5*3 GG型患者FK506的C和C/D在术后7、14、21、28 d均显著高于CYP3A5*3 AA型和AG型患者（P<0.01）。POR*28 CT型患者术后21 d和28 d的C/D与CC型患者相比具有显著性差异（P<0.05）,而POR*28基因型对其他各时间点FK506的C、D以及C/D均无影响。根据CYP3A5*3基因分层后发现,POR*28基因多态性对CYP3A5*3 AA型患者FK506的C、D以及C/D影响最大,其次是CYP3A5*3 AG型,而对CYP3A5*3 GG型患者各时间点的C、D以及C/D均无影响。在CYP3A5*3 AA型患者中,术后各时间点POR*28 CC型FK506的D均低于CT和TT型患者,CC型患者的C/D均高于CT型和TT型,且在多个时间点处有统计学差异。结论：肾移植初期,CYP3A5*3和POR*28基因多态性对FK506的浓度剂量有影响,且POR*28基因多态性对CYP3A5*3 AA型患者FK506浓度剂量的影响最大。     

肾移植患者CYP3A5*3基因多态性对他克莫司血药浓度/剂量比和疗效的影响

目的:研究肾移植术后患者CYP3A5*3基因多态性对他克莫司(FK506)血药浓度/剂量比(C/D)及急性排斥反应和不良反应的影响。方法:采用聚合酶链反应(PCR)和限制性内切片段长度多态性(RFLP)的方法检测肾移植患者CYP3A5*3基因型,比较不同基因型患者之间FK506的C/D值以及急性排斥反应(AR)、不良反应的差异。结果:肾移植术后1个月内,*3/*3型患者FK506的C/D值为151.7±60.0,显著高于*1/*1型和*1/*3型患者的72.6±21.7和99.4±40.3(P<0.01);移植术后3个月内*1/*1型患者AR的发生率为25.0%,显著高于*1/*3型和*3/*3型患者的10.8%和8.8%(P<0.05);而术后肝功能异常、高血糖、药物肾毒性等不良反应发生率*1/*3型和*3/*3型显著高于*1/*1型患者(P<0.05)。结论:CYP3A5*3基因多态性与肾移植患者FK506的C/D值及急性排斥反应(AR)、不良反应密切相关。     

CYP3A5~*3和CYP3A4~*18B基因多态性对肾移植患者环孢素药代动力学的影响

目的回顾性研究肾脏移植后1mon,CYP3A5*3和CYP3A4*18B基因多态性对CsA药代动力学参数的影响。方法采用PCR-RFLP方法分析了63名肾脏移植患者CYP3A5*3和CYP3A4*18B基因型;荧光偏正免疫法用于检测肾移植患者静脉全血中的CsA浓度。结果在63名肾移植患者中,CYP3A5*3和CYP3A4*18B突变等位基因发生频率分别为0.770(95CI:0.767～0.773),0.235(95CI:0.235～0.241),而且这些等位基因表现出完全连锁不平衡。在移植术后1mon内,携带CYP3A4*1/*1野生型纯合子患者的C0以及剂量校正谷血浓度(C0/D)均明显高于携带CYP3A4*1/*18B杂合子或CYP3A4*18B/*18B突变型纯合子患者(P<0.05,Mann-WhitneyUtest);CYP3A5*1/*1基因型组的给药剂量明显高于CYP3A5*1/*3或CYP3A5*3/*3基因型组(P=0.004<0.01,Kruakal-Wallistest);CYP34*18B和CYP3A5*3联合考虑,对于CYP3A5表达组,同样发现C0、C0/D在CYP3A4*1/*1组C0以及C0/D均明显高于CYP3A4*1/*18B或CYP3A4*18B/*18B组(P<0.05,Mann-WhitneyUtest);而其他药动学参数在CYP3A5*3及CYP3A4*18B各组间相比差异则没有统计学意义。结论CYP3A5*3和(或)CYP3A4*18B基因多态性对肾移植后1monCsA药代动力学有一定影响,移植前CYP3A5*3基因型的分析仍需进一步研究。     

Tacrolimus and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors: An interaction study in CYP3A5 non-expressors, renal transplant recipients

Objectives:

Atherosclerosis is a significant factor affecting long-term outcome in renal transplant recipients. Studies have been conducted to determine the pharmacogenomic pathways involved in statin efficacy, efficiency, and adverse effect likelihood. However, little is known about the influence of statins on tacrolimus kinetics. The aim of this study was to investigate possible pharmacological interactions between tacrolimus and statins in CYP3A5 non-expressors, renal transplant recipients.

Materials and Methods:

Twenty-four patients, treated with tacrolimus (n=24), methylprednisolone (n=24), and mycophenolate mofetil (n=19)/azathioprine (n=1)/everolimus (n=4), participated in the study. After an observation time of 112±36 days, statins, namely, atorvastatin (n=12), simvastatin (n=8), pravastatin (n=2), or fluvastatin (n=2), were administered for additional 101±34 days. DNA was extracted from whole blood sample and polymerase chain reaction followed by restriction fragment length polymorphism analysis was used for CYP3A5 genotyping. Student''s t-test and Mann-Whitney test were used to test the significance of difference in variables that passed or did not pass Kolmogorov''s normality test, respectively.

Results:

No statistically significant difference was observed in tacrolimus daily dose, concentration, concentration/dose ratio, and volume of distribution before and during the administration of statins. Statistically significant decrease in serum cholesterol was observed after initiation of statins. Renal and hepatic function remained unchanged and no skeletal muscle abnormalities were reported.

Conclusions:

The results of this study show that tacrolimus and statins do not interact in terms of efficacy, efficiency, and adverse effect likelihood. No significant clinical interaction or effect was observed, even with the use of atorvastatin or simvastatin, which are metabolized by CYP3A4 such as tacrolimus.     

Influence of the CYP3A5 and MDR1 genetic polymorphisms on the pharmacokinetics of tacrolimus in healthy Korean subjects

AIMS: To determine the frequencies of the genotypes of CYP3A5 and MDR1 and to examine the influence of the polymorphisms of these genes on tacrolimus pharmacokinetics in the Korean population. METHODS: Twenty-nine healthy Koreans who participated in the previous tacrolimus pharmacokinetic study were genotyped for CYP3A4*1B, CYP3A5*3, MDR1 c.1236C-->T, MDR1 c.2677G-->A/T and MDR1 c.3435C-->T. The relationship between the genotypes so obtained and tacrolimus pharmacokinetics observed in the previous study was examined. RESULTS: No subject in this study had the CYP3A4*1B variant. The observed frequencies of CYP3A5*1/*1, *1/*3, and *3/*3 were 0.069 [confidence interval (CI) -0.023, 0.161], 0.483 (CI 0.301, 0.665) and 0.448 (CI 0.267, 0.629), respectively. AUC(0-infinity) for the CYP3A5*1/*1 or *1/*3 genotype was 131.5 +/- 44.8 ng h ml(-1) (CI 109.6, 153.5), which was much lower compared with the CYP3A5*3/*3 genotype of 323.8 +/- 129.3 ng h ml(-1) (CI 253.5, 394.1) (P = 2.063E-07). Similarly, C(max) for the CYP3A5*1/*1 or *1/*3 genotype was 11.8 +/- 3.4 ng ml(-1) (CI 10.1, 13.5), which was also much lower compared with the CYP3A5*3/*3 genotype of 24.4 +/- 12.3 ng ml(-1) (CI 17.8, 31.1) (P = 0.0001). However, there was no significant difference in tacrolimus pharmacokinetics among the MDR1 diplotypes of CGC-CGC, CGC-TTT, CGC-TGC, TTT-TGC or TTT-TTT (P = 0.2486). CONCLUSIONS: This study shows that the CYP3A5*3 genetic polymorphisms may be associated with the individual difference in tacrolimus pharmacokinetics. An individualized dosage regimen design incorporating such genetic information would help increase clinical efficacy of the drug while reducing adverse drug reactions.     

CYP3A5*3基因多态性与肾移植患者围手术期他克莫司相关不良反应的关系

目的：明确细胞色素P450（Cytochrome P450,CYP）3A5*3基因多态性与肾移植患者围手术期他克莫司相关不良反应的关系。方法：选取2014年11月至2018年3月于某院行肾移植术且术后应用他克莫司的患者170例,检测其CYP3A5*3基因型,记录患者肾移植术后入院期间的用药情况、各项临床指标及他克莫司相关不良反应的发生情况。比较不同CYP3A5*3基因型患者间他克莫司相关不良反应发生率。结果：CYP3A5*1是肾移植患者发生他克莫司相关移植后高脂血症的保护因子,CYP3A5表达型患者发生移植后高脂血症的风险仅为非表达者的0.465倍（95% CI：0.217~0.996,P=0.049）。结论：CYP3A5*3基因多态性与肾移植患者发生他克莫司相关移植后高脂血症的风险显著相关,其机制可能与与CYP3A5非表达型患者对他克莫司的代谢能力较低,使其在体内积蓄有关。