Association study of ABCB1 and CYP3A5 gene polymorphisms with sirolimus trough concentration and dose requirements in Chinese renal transplant recipients

The objective of this study was to investigate the possible association of the ABCB1 gene C3435 T polymorphism and the CYP3A5 gene A6986G polymorphism with sirolimus (SRL) trough concentration and dose requirements in Chinese stable renal transplant recipients. Blood samples were collected from 105 healthy volunteers and 50 renal transplant patients, whose polymorphisms of the ABCB1 and CYP3A5 genes were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). Plasma concentrations of SRL were determined with HPLC. The allele frequencies of the ABCB1 mutation in Chinese healthy volunteers and renal transplant recipients were 51.0% and 44.0% (p>0.05), while the allele frequencies of the CYP3A5 mutation were 72.9% and 71.0% (p>0.05). The SRL concentration/dose ratio (C/D) in patients with CYP3A5 (*)3/(*)3 were significantly higher than that of those with (*)1 allele (p<0.05). However, no significant differences were observed between C/D and ABCB1 SNPs (p>0.05). These results confirm that when treated with a SRL-based therapy and low-dose steroids, patients carrying the CYP3A5(*)1 allele required significantly more SRL to achieve adequate blood trough concentrations. In patients with SRL-based therapy, genotyping of the CYP3A5 genes may help to optimize the SRL management in renal transplant recipients.     

Influence of the MDR1 haplotype and CYP3A5 genotypes on cyclosporine blood level in Chinese renal transplant recipients

1. The purpose of the study was to elucidate the influence of multidrug resistance gene (MDR1) haplotype and CYP3A5 genotype on cyclosporine (CsA) blood level in Chinese renal transplant recipients.

2. CsA trough level (C₀) and peak level (C₂) of 115 patients 1 week and 1 month after renal transplantation were determined. MDR1 C1236T, G2677T/A, C3435T and CYP3A5*3 genotypes were determined by polymerase chain reaction (PCR) assays based on amplification refractory mutation.

3. Dose-adjusted C₀ (C₀/D), C₂ (C₂/D) were 50.5?±?22.5, 267.8?±?110.1 ng·kg·(ml·mg)^?1 after 1 week of therapy, and 79.3?±?29.4, 406.0?±?135.3 ng·kg·(ml·mg)^?1 after 1 month of therapy. Frequencies of MDR1 haplotype TTT, CGC, and TGC were 27.0%, 25.2% and 20.0%, respectively. After 1 month of therapy, C₂/D of TTT/TTT patients were 30% (p = 0.057) and 53% (p = 0.003) higher than CGC/TTT and CGC/CGC patients. C₀/D of CYP3A5 *1/*1, *1/*3 and *3/*3 patients after 1 month of therapy were 51.8?±?25.0, 71.5?±?27.6, and 86.7?±?28.6 ng·kg·(ml·mg)^?1 (p < 0.05).

4. MDR1 haplotypes and CYP3A5*3 genotypes can be related to C₂ and C₀ of CsA, respectively.

     

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.     

Population pharmacokinetics of sirolimus in de novo Chinese adult renal transplant patients

AIMS

This study was aimed at determining the population pharmacokinetics of sirolimus and identifying factors that explain pharmacokinetic variability in de novo Chinese adult renal transplant patients.

METHODS

Data were retrospectively extracted from a formal multicentre clinical trial, which was originally designed to evaluate the safety and efficacy of ciclosporin dose reduction and ciclosporin elimination in patients receiving sirolimus. All patients received 12-month treatment, i.e. induction therapy with ciclosporin, sirolimus and corticosteroids during the first 3 months followed by either ciclosporin dose reduction or ciclosporin discontinuation thereafter. Eight-hundred and four sirolimus trough blood concentrations (C₀) from 112 patients were used to develop a population pharmacokinetic model using the nonmem program. A one-compartment model with first-order absorption and elimination was selected as the base model. The influence of demographic characteristics, biochemical and haematological indices, ciclosporin daily dose, ciclosporin C₀ as well as other commonly used co-medications were explored.

RESULTS

The typical values with interindividual variability for apparent clearance (CL/F) and apparent volume of distribution (V/F) were 10.1 l h⁻¹ (23.8%) and 3670 l (56.7%), respectively. The residual variability was 29.9%. CL/F decreased significantly with silymarin or glycyrrhizin co-therapy in hepatically impaired patients, and with increasing total cholesterol levels or ciclosporin C₀. Moreover, CL/F increased nonlinearly with increasing sirolimus daily dose. The median parameter estimates from a nonparametric bootstrap procedure were comparable and within 5% of the estimates from nonmem.

CONCLUSIONS

These results provide important information for clinicians to optimize sirolimus regimens in Chinese renal transplant patients.     

CYP3A5~* 3基因多态性与肾移植术后环孢素肝损伤的相关性

目的:研究肾移植术后患者CYP3A5*3基因多态性对环孢素(CsA)所致肝损伤的影响。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359名肾移植患者进行CYP3A5*3基因型检测;荧光偏振免疫法检测肾移植患者CsA血浓度,根据肾移植患者发生肝脏损伤的情况分为CsA肝损伤组、其他原因肝损伤组和对照组。结果:在359名肾移植患者中,CYP3A5*3突变等位基因频率为73.5%。与对照组相比,CsA肝损伤组和其他原因肝损伤组的CYP3A5*3/*3分布频率明显增高(P<0.05或0.01),CsA肝损伤组的CYP3A5*3/*3分布频率亦明显高于其他原因肝损伤组(P<0.01)。肾移植术后1个月和3个月,CYP3A5*3/*3组和*1/*3组的CsA血谷浓度均明显高于*1/*1组(P<0.05)。术后7d、1个月、3个月、6个月,CsA肝损伤组的CsA谷浓度明显高于对照组(P<0.05或P<0.01)。Logistic回归模型显示,*3/*3基因型和术后6个月高CsA谷浓度是CsA肝损伤发生的危险因素。结论:CYP3A5*3基因多态性对肾移植患者CsA所致肝损伤有明显影响,携带*3突变基因...     

Effects of CYP3A5 genotypes,ABCB1 C3435T and G2677T/A polymorphism on pharmacokinetics of Tacrolimus in Chinese adult liver transplant patients

Abstract

1.?The purpose of this study was to establish a population pharmacokinetic (PK) model of tacrolimus and evaluate the influence of clinical covariates, including the genetic polymorphisms of the cytochrome P450 3A5 gene (CYP3A5) and gene-encoding P-glycoprotein (ABCB1), on the PK parameters in Chinese adult liver transplant recipients.

2.?Details of drug dose, sampling times and concentrations were collected retrospectively from routine therapeutic drug monitoring data early after liver transplant. Tacrolimus PKs was studied by a non-linear mixed-effect modeling (NONMEM) method. CYP3A5 genotypes, ABCB1 C3435T and G2677T/A polymorphism and a number of clinical covariates were tested for their influence on TAC PKs.

3.?A one-compartment model with first-order absorption and elimination adequately described the data. Apparent clearance (CL/F) and apparent volumes of distribution (V/F) in final population model were 17.6?L/h and 225?L, respectively. The absorption rate constant (K_a) was fixed at 4.48?h^?1. The inter-individual variability in CL/F and V/F was 53.9 and 68%, respectively. In the final model, CYP3A5 genotype, post-operative day, alanine aminotransferase, total bilirubin, hematocrit and blood urea nitrogen were found to significantly influence the CL/F, whereas POD and HB influence V/F.

4.?Population PK analysis of tacrolimus in Chinese adult liver transplant patients resulted in identification of the CYP3A5 genotype, POD, BUN, ALP, HCT, TBIL and HB as significant covariates on the PK parameters of tacrolimus.     

CYP 3A5*3基因多态性对肾移植术后他克莫司药代动力学的影响

目的探讨CYP3A5*3基因多态性对肾移植术后他克莫司(免疫抑制药)剂量校正给药2h后浓度的影响。方法选取61例肾移植术后患者,用聚合酶链式反应-限制性片段长度多态性的方法,分析CYP 3A5*3基因型;用微粒酶联免疫吸附法,测定患者他克莫司浓度。并分析CYP 3A5*3基因多态性与他克莫司给药剂量、给药2h浓度(C2)及剂量校正给药2h后浓度(C2/D)的相关性。结果肾移植术后1周及1、3个月,CYP 3A5*1/*1 CYP 3A5*1/*3组和CYP3A5*3/*3组他克莫司剂量比较均无显著性差异。术后1周和1个月,2组间他克莫司C2比较无显著性差异;术后3个月,CYP 3A5*1/*1 CYP 3A5*1/*3组的C2显著低于CYP 3A5*3/*3组(P<0.05)。术后1周及1、3个月,CYP 3A5*1/*1 CYP 3A5*1/*3组的C2/D均明显低于CYP 3A5*3/*3组(P<0.05)。结论肾移植术后,他克莫司C2/D的个体化差异与患者CYP3A5*3基因型密切相关。     

肾移植病人西罗莫司血药浓度/剂量比与CYP3A5基因多态性的关系

目的:研究肾移植术后病人CYP3A5基因多态性与免疫抑制剂西罗莫司临床个体化给药剂量的关系。方法:采用聚合酶链反应(PCR)和限制性内切片段多态性(RFLP)的方法对105例健康受试者和50例肾移植术后病人进行CYP3A5基因分型。使用高效液相色谱(HPLC)测定病人的西罗莫司血药浓度。比较不同基因型之间的西罗莫司的血药浓度与每千克体重的剂量(C/D)比值的差异。结果:健康受试者和肾移植病人的CYP3A5 A6986G SNPs,CYP3A5*3的发生频率分别为72.9％和71％,差异无显著意义(P>0.05)。肾移植*1/*3型病人的C/D比值(362±s108)μg·L~(-1)per mg·kg~(-1)和*3/*3型病人的C/D比值(375±123)μg·L~(-1)per mg·kg~(-1)差异无显著意义(P>0.05),但两者C/D值均明显高于*1/*1型病人(199±65)μxg·L~(-1)per mg·kg~(-1),差异具有显著意义(P<0.05)。结论:肾移植病人的CYP3A5基因多态性与西罗莫司血药浓度具有相关性,*1/*3型和*3/*3型病人拟取得相似的血药浓度要比*1/*1型病人服用更低剂量的西罗莫司。研究肾移植病人的CYP3A5基因型,有利于肾移植病人术后西罗莫司个体化用药方案的制定。     

Association of CYP3A polymorphisms with the pharmacokinetics of cyclosporine A in early post-renal transplant recipients in China

Aim:

To evaluate retrospectively the association of cytochrome P450 3A (CYP3A) and ATP-binding cassette sub-family B member 1 (ABCB1) gene polymorphisms with the pharmacokinetics of cyclosporine A (CsA) in Chinese renal transplant patients.

Methods:

One hundred and twenty-six renal transplant patients were recruited. Blood samples were collected, and corresponding clinical indices were recorded on the seventh day after the procedure. The patients were genotyped for CYP3A4*1G, CYP3A5*3C, ABCB1 1236 C>T, ABCB1 2677 G>T/A, and ABCB1 3435 C>T polymorphisms. Whole blood trough concentrations of CsA at time zero (C₀) were measured before the drug administration. A multiple regression model was developed to analyze the effects of genetic factors on the CsA dose-adjusted C₀ (C₀/dose) based on several clinical indices.

Results:

The CYP3A5*3C polymorphism influenced the C₀ and C₀/dose of CsA, which were significantly higher in patients with the GG genotype than in patients with the AA or GA genotypes. No significant differences were detected for other SNPs (CYP3A4*1G, ABCB1 1236 C>T, ABCB1 2677 G>T/A, and ABCB1 3435 C>T). In a univariate analysis using Pearson''s correlation test, age, hemoglobin, blood urea nitrogen and blood creatinine levels were significantly correlated with the log-transformed CsA C₀/dose. In the multiple regression model, CYP3A5*3C, age, hemoglobin and blood creatinine level were associated with the log-transformed CsA C₀/dose.

Conclusion:

CYP3A5*3C correlates with the C₀/dose of CsA on the seventh day after renal transplantation. The allele is a putative indicator for the optimal CsA dosage in the early phase of renal transplantation in the Chinese population.     

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、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。     

Recipient ABCB1, donor and recipient CYP3A5 genotypes influence tacrolimus pharmacokinetics in liver transplant cases

BackgroundEffective immunosuppression through optimization of trough levels tacrolimus reduces post-transplant mortality rate in liver transplant cases.MethodsMeta-analysis was carried out to evaluate how donor/recipient CYP3A5 (n = 678) and recipient ABCB1 (n = 318) genotypes influence tacrolimus pharmacokinetics till one-month of transplantation.ResultsThe donor CYP3A5*3/*3 genotype exhibited higher concentration/dose (C/D) ratio of tacrolimus in week 1 (mean difference: 65.04, 95% CI: 15.30–114.79 ng/ml/mg/kg), week 2 (mean difference: 21.7, 95% CI: 12.6–30.9 ng/ml/mg/kg) and week 4 (mean difference: 43.28, 95% CI: 17.09 – 69.49 ng/ml/mg/kg) compared to *1/*1 and *1/*3 genotypes. The recipient CYP3A5 *3/*3 genotype did not showed significant difference in tacrolimus C/D ratio in week 1 compared to other two genotypes. However, week 2 (mean difference: 44.16, 95% CI: 3.68–84.65 ng/ml/mg/kg) and week 4 (mean difference: 43.74, 95% CI: 12.50–75.00 ng/ml/mg/kg) availability was higher in *3/*3 mutant recipients. However, the recipient ABCB1 3435 C > T polymorphism has no significant influence on tacrolimus pharmacokinetics till one month of transplant.ConclusionsThe donor and recipient CYP3A5*3 polymorphism influences tacrolimus pharmacokinetics in the first month post-transplantation, whereas the association with recipient ABCB1 3435 C > T is inconclusive.     

CYP3A4/5、ABCB1基因单倍型与中国肾移植患者他克莫司血药谷浓度相关性的研究

目的:探讨CYP3A4*18B、CYP3A5*3、ABCB1基因单倍型对中国肾移植患者术后一月内他克莫司谷浓度(C0/D)的影响。方法:采用限制性片段长度多态性技术分析46名肾移植患者CYP3A4*18B、CYP3A5*3、ABCB1(外显子C1236T、G2677A/T、C3435T)基因型,采用酶增强免疫测定技术测定患者C0值。结果:经分析患者CYP3A4*18B、CYP3A5*3、ABCB1(C1236T,G2677A/T,C3435T)等位基因频率分别为0.304、0.707、0.554、0.478和0.304,均符合HardyWeinberg平衡。CYP3A4-3A5、G2677A/T-C3435T及C1236T-C3435T间均表现为连锁不平衡。术后8~15、16~30天内CYP3A4*18B与患者FK506 C0/D值显著相关,野生型患者C0/D值分别为杂合及突变型患者的1.34和1.67倍。CYP3A5*3基因也与患者FK506 C0/D值显著相关。突变型患者C0/D值在术后1~7、8~15及16~30天时分别为野生及杂合型患者的1.56、1.98及1.99倍。单倍型分析发现CYP3A4/5单倍型GG型携带者C0/D值较非携带者在移植术后8~15、16~30天显著性增加1.43、1.77倍。未观察到ABCB1基因多态性及单倍型对FK506血药浓度的影响。结论:仅CYP3A4/5单倍型与他克莫司C0/D值显著相关,移植前对CYP3A4/5单倍型进行检测将有利于他克莫司给药剂量的调整。     

服用他克莫司的肾移植患者ABCB1基因多态性与术后感染的相关性

目的:观察服用他克莫司(Tacrolimus)的肾移植受者ABCB1基因多态性对于术后感染发生的影响。方法:选取行肾移植手术并服用他克莫司的患者90例,根据术后是否存在感染分为感染组和对照组,检测所有患者的ABCB1基因型3435C>T,1236C>T和2677G>A/T。采用χ²检验,方差分析和独立样本T检验的方法对患者的基本临床资料进行检验。采用卡方检验比较感染组和未感染组的基因多态性频率分布差异。结果:患者C1236T,C3435T,G2677A/T等位基因频率,均符合Hardy-Weinberg平衡。感染组和非感染组患者的年龄,性别,体质量,临床诊断,吗替麦考酚酯(Mycophenolate Mofetil)的用量均没有显著性差异。2组患者的平均血药谷浓度在一年内均无统计学差异。C1236T单核苷酸多态性对肾移植术后感染发生的影响具有统计学意义(P=0.034)。G2677A/T突变的发生对肾移植术后感染发生的影响具有统计学意义(P=0.010)。结论:ABCB1基因多态性中,仅C1236T的SNP多态性与G2677A/T的突变对肾移植术后感染发生的影响具有统计学意义。     

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.     

Prediction of tacrolimus metabolism and dosage requirements based on CYP3A4 phenotype and CYP3A5*3 genotype in Chinese renal transplant recipients

Aim:

To examine how the endogenous CYP3A4 phenotype and CYP3A5^*3 genotype of Chinese renal transplant recipients influenced the dose-corrected trough concentration (C₀/D) and weight-corrected daily dose (D/W) of tacrolimus.

Methods:

A total of 101 medically stable kidney transplant recipients were enrolled, and their blood and urine samples were gathered. The endogenous CYP3A4 phenotype was assessed by the ratio of 6β-hydroxycortisol and 6β-hydroxycortisone to cortisol and cortisone in urine. CYP3A5^*3 genotype was determined using PCR-RELP.

Results:

In overall renal transplant recipients, a multiple regression analysis including the endogenous CYP3A4 phenotype, CYP3A5^*3 genotype and post-operative period accounted for 60.1% of the variability in C₀/D ratio; a regression equation consisting of the endogenous CYP3A4 phenotype, post-operative period, body mass index, CYP3A5^*3 genotype, gender, total bilirubin and age explained 61.0% of the variability in D/W ratio. In CYP3A5^*3/^*3 subjects, a combination of the endogenous CYP3A4 phenotype, post-operative period and age was responsible for 65.3% of the variability in C₀/D ratio; a predictive equation including the endogenous CYP3A4 phenotype, post-operative period, body mass index, gender and age explained 61.2% of the variability in the D/W ratio. Base on desired target range of tacrolimus trough concentrations, individual daily dosage regimen was calculated, and all the observed daily doses were within the predicted range.

Conclusion:

This study provides the equations to predict tacrolimus metabolism and dosage requirements based on the endogenous CYP3A4 phenotype, CYP3A5^*3 genotype and other non-genetic variables.     

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。     

Associations of ABCB1, NFKB1, CYP3A,and NR1I2 polymorphisms with cyclosporine trough concentrations in Chinese renal transplant recipients

Aim:

Cyclosporine requires close therapeutic drug monitoring because of its narrow therapeutic index and marked inter-individual pharmacokinetic variation. In this study, we investigated the associations of CYP3A4, CYP3A5, ABCB1, NFKB1, and NR1I2 polymorphisms with cyclosporine concentrations in Chinese renal transplant recipients in the early period after renal transplantation.

Methods:

A total of 101 renal transplant recipients receiving cyclosporine were genotyped for CYP3A4^*1G, CYP3A5^*3, ABCB1 C1236T, G2677T/A, C3435T, NFKB1 −94 ins/del ATTG, and NR1I2 polymorphisms. Cyclosporine whole blood levels were measured by a fluorescence polarization immunoassay. Trough concentrations of cyclosporine were determined for days 7-18 following transplantation.

Results:

The dose-adjusted trough concentration (C₀) of cyclosporine in ABCB1 2677 TT carriers was significantly higher than that in GG carriers together with GT carriers [90.4±24.5 vs 67.8±26.8 (ng/mL)/(mg/kg), P=0.001]. ABCB1 3435 TT carriers had a significantly higher dose-adjusted C₀ of cyclosporine than CC carriers together with CT carriers [92.0±24.0 vs 68.4±26.5 (ng/mL)/(mg/kg), P=0.002]. Carriers of the ABCB1 1236TT-2677TT-3435TT haplotype had a considerably higher CsA C₀/D than carriers of other genotypes [97.2±21.8 vs 68.7±26.9 (ng/mL)/(mg/kg), P=0.001]. Among non-carriers of the ABCB1 2677 TT and 3435 TT genotypes, patients with the NFKB1 −94 ATTG ins/ins genotype had a significantly higher dose-adjusted C₀ than those with the −94 ATTG del/del genotype [75.9±32.9 vs 55.1±15.1 (ng/mL)/(mg/kg), P=0.026].

Conclusion:

These results illustrate that the ABCB1 and NFKB1 genotypes are closely correlated with cyclosporine trough concentrations, suggesting that these SNPs are useful for determining the appropriate dose of cyclosporine.     

CYP3A5 rather than MDR1 gene polymorphism of recipient is related to tacrolimus individual dose requirement in Chinese liver transplant patients

AIM： Tacrolimus shows considerable interindividual pharmacokinetic variability, therapeutic drug monitoring of trough blood concentration is necessary to avoid adverse effects. CYP3A5 and P-glycoprotein （P-gp, encoded by MDR1） are involved in tacrolimus＇ metabolism and absorption process. This study is to investigate whether tacrolimus dosage adjustment is affected by the polymorphism in CYP3A5 and MDR1 in Chinese liver transplant patients. METHODS： Forty-nine liver transplant patients treated with tacrolimus were enrolled in this study. Polymerase chain reaction-restriction fragment length polymorphism （PCR-RFLP） analysis was applied to determine the genotype of CYP3A5 and MDR1. Tacrolimus blood tough concentration was measured by FPIA, and concentration/dose ratio（C/D） was investigated at day 7, day 14 and 1 month after liver transplantation.[第一段]