CYP3A5 genotype is associated with elevated blood pressure

The present study aimed to determine whether a polymorphism in CYP3A5, encoding the major CYP3A enzyme in the human kidney, is associated with blood pressure in Caucasians. A homogenous group of 115 young, white male students with normal or mildly elevated, but untreated blood pressure was included. Blood pressure was recorded by ambulatory 24-h blood pressure-monitoring and compared between individuals with high (*1/*3) and low CYP3A5 expression (*3/*3). Moreover, genotype-dependent differences in parameters associated with the renin-angiotensin-aldosterone system were evaluated. Twenty-four hour diastolic blood pressure values were not significantly different between the two groups. However, individuals with the CYP3A5*3/*3 genotype had significantly higher 24-h ambulatory systolic blood pressure values compared to subjects with the CYP3A5*1/*3 genotype (129+/-10 versus 124+/-9, P < 0.05). There was no association of CYP3A5 genotype with angiotensin II plasma concentrations, renal plasma flow, glomerular filtration rate, urinary sodium excretion and parameters determined by echocardiography, but the *3/*3 group had significantly lower serum aldosterone concentrations compared to the individuals with the *1/*3 genotype (101+/-29 versus 117+/-29 pg/ml, P < 0.05). These data, as generated with a homogenous population of young Caucasians, indicate that the CYP3A5 genotype affects blood pressure in humans possibly by genotype-dependent differences in renal, CYP3A5-mediated metabolism of cortisol and/or aldosterone. We interpret the lower serum aldosterone concentration in the genotype group with the elevated systolic blood pressure as a counter-regulatory mechanism to attenuate the increased blood pressure associated with the CYP3A5*3/*3 genotype.     

Cyclosporin A absorption profiles in pediatric renal transplant recipients predict the risk of acute rejection

The current focus of cyclosporin A (CsA) monitoring in adult transplantation for optimized immunosuppression is on the early portion of the CsA area under the concentration-time curve (AUC), particularly in the first 4 hours postdose, designated as AUC(0-4), and on the blood concentration 2 hours postdose (C2) as a highly predictive marker for AUC(0-4). Because data in pediatric patients are scarce, full-time (12 hours) and absorption profiles of CsA were analyzed in relation to CsA effectiveness in 61 pediatric renal transplant recipients aged 3.2 to 17.4 years on an immunosuppressive triple regimen with CsA, mycophenolate mofetil, and methylprednisolone. CsA dosing was based on body surface area and adjusted to CsA trough levels. Pharmacokinetic (PK) profiles were obtained 1 and 3 weeks (initial period) and 3 and 6 months posttransplant (stable period). Patients with an AUC(0-4) < 4400 microg x h/L at both PK sampling periods in the first 3 weeks posttransplant had an adjusted relative risk of 48.4% to suffer an acute rejection episode (ARE), whereas in patients with at least 1 AUC0-4 above this threshold, the adjusted relative risk for an ARE was only 13.1% (P < 0.02). The single PK parameters C0 or C2 did not discriminate between patients with and without acute rejection. The PK parameters C1.25 (r2 = 0.64) or C2 (r2 = 0.60) showed a stronger relationship to the absorption profile (AUC(0-4)) than C0 (r2 = 0.15). An abbreviated profile consisting of the PK variables C(0.5;2) or C(0;0.5;2) showed the closest correlation to the absorption profile (r2 = 0.89) and the lowest percentage prediction error. These data indicate that absorption profiling in pediatric renal transplant recipients has the potential to optimize immunosuppressive therapy with CsA.     

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.     

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。     

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。     

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...     

<Emphasis Type="Italic">CYP3A5 *1</Emphasis> allele associated with tacrolimus trough concentrations but not subclinical acute rejection or chronic allograft nephropathy in Japanese renal transplant recipients

Purpose  We assessed reported associations of CYP3A5 *1 allele with a delay in achieving target tacrolimus concentrations, and occurrence of biopsy-confirmed subclinical acute rejection (SAR) and chronic allograft nephropathy (CAN) in Japanese subjects. Methods  Forty-one renal allograft recipients were studied. The targeted tacrolimus trough concentrations were 20–25 ng/mL up to 2 weeks post-transplantation, 10–15 ng/mL up to 6 weeks, and 5–10 ng/mL thereafter. At 1 month and 1 year post-transplantation, allograft biopsies were performed. Results  The CYP3A5 *1/*1 + *1/*3 (expresser) and *3/*3 (nonexpresser) alleles were detected in 19 and 22 patients, respectively. Although the mean trough concentrations were lower in CYP3A5 expressers than nonexpressers for the first 3 weeks, no difference in frequency of SAR among CYP3A5 genotypes was found. The mean trough concentrations were lower from 8 to 12 months post-transplantation, and the frequency of CAN was lower in CYP3A5 expressers. Conclusions  In contrast to the previous reports, the CYP3A5 *1 allele was not associated with the frequency of SAR or CAN, suggesting that further studies of different immunosuppressive strategies using tacrolimus are needed to confirm the adequate dosing and concentration of tacrolimus for each CYP3A5 genotype.     

CYP3A5基因型对中国肾移植术后患者体内他克莫司缓释剂型药动学参数的影响

目的研究CYP3A5基因型对中国肾移植术后患者体内他克莫司缓释剂型药动学参数的影响。方法采用化学发光免疫法检测20例肾移植术后患者在服用缓释(10例)和普通剂型(10例)他克莫司后的全血浓度;采用聚合酶链反应-限制性片段长度多态法检测服用缓释剂型他克莫司患者的CYP3A5基因型;缓释剂型组检测0~24 h的11个时间点的血药浓度,而普通剂型检测0~12 h内的10个时间点的血药浓度。结果无剂量校正的缓释剂型组的AUC_(0~24 h)为普通剂型组AUC_(0~12 h)的1.78倍,有剂量校正的缓释剂型组的C_0为普通剂型的60%,其余药动学参数差异无显著性;缓释剂型中慢代谢型组的C_(max)、AUC_(0~24 h)和C_0分别为快代谢型组的1.75、1.96、2.49倍(无剂量校正)以及1.80、2.34和2.64倍(有剂量校正);缓释剂型组的C_0与AUC_(0~24 h)的相关性良好。结论他克莫司普通剂型转换至缓释剂型时应该注意上调给药剂量,同时缓释剂型应结合CYP3A5的基因型检测,确保C_0值在治疗窗范围内。     

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.     

Association of MDR1, CYP3A4*18B, and CYP3A5*3 polymorphisms with cyclosporine pharmacokinetics in Chinese renal transplant recipients

Objective  The objective of this study was to retrospectively evaluate the effects of MDR1, CYP3A4*18B, and CYP3A5*3 genetic polymorphisms on cyclosporine A (CsA) pharmacokinetics in Chinese renal transplant patients during the first month after transplantation. Methods  A total of 103 renal transplant recipients receiving CsA were genotyped for MDR1 (C1236T, G2677T/A, and C3435T), CYP3A4*18B, and CYP3A5*3. The predose and 2-h postdose concentrations of CsA (C₀ and C₂, respectively) were determined by fluorescence polarization immunoassay, and their relationships with corresponding genotypes and haplotypes were investigated. Results  Patients with a CYP3A4*1/*1 genotype were found to have a higher dose-adjusted concentration compared with those with CYP3A4*18B/*18B, as follows: for C₂, 19.3% (P = 0.008) during days 8-15, 35.2% (P = 0.008) during days 16–30, and for C₀, 39.7% (P = 0.012) during days 16–30. The dose-adjusted C₀ was higher in patients with MDR1 1236CC compared with those with 1236TT in the first month postoperation. The dose-adjusted C₀ in patients with the CYP3A5*3/*3 genotype was 25.5% and 30.7% higher than those with the wild-type genotype during days 8–15 (P = 0.011) and days 16–30 (P = 0.015), respectively. Haplotype analysis revealed that the dose-adjusted C₀ was higher in the first month following surgery in carriers of haplotype MDR1 CAC than in noncarriers. Polymorphisms of MDR1 and CYP3A5*3 did not affect dose-adjusted C_2. Conclusion  The data suggests that the CYP3A4*18B genotype affects CsA pharmacokinetics during the first month following surgery in Chinese renal transplant recipients. Patients with CYP3A4*18B alleles may require higher doses of CsA to reach the target levels. Large prospective studies may be needed to further explore the impact of MDR1 and CYP3A5*3 polymorphisms on CsA pharmacokinetics in renal transplant recipients.     

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.     

Daclizumab: a review of its use in the prevention of acute rejection in renal transplant recipients

The humanised monoclonal antibody daclizumab is an immunosuppressive agent that reduces acute rejection in renal transplant recipients. It is specific for the alpha subunit (Tac/CD25) of the interleukin-2 (IL-2) receptor on activated T cells and achieves immunosuppression by competitive antagonism of IL-2-induced T cell proliferation. Daclizumab has advantages over murine antibodies to the IL-2 receptor, including improved effector function, a low potential for immunogenicity and long elimination half-life. When added to standard cyclosporin-based immunosuppressive therapy with or without azathioprine, daclizumab (1 mg/kg prior to surgery and once every 2 weeks thereafter for a total of 5 doses) significantly reduced the 6-month rate of acute rejection compared with placebo in 2 phase III studies. The mean number of rejection episodes was significantly reduced and the time to first acute rejection significantly increased in daclizumab versus placebo recipients. Patient survival at 1 year after transplantation was significantly higher with daclizumab than placebo in 1 study and showed a trend in favour of the drug in the other study. The 1-year graft survival rate tended to be greater in daclizumab than in placebo recipients in both studies, In a phase II study, acute rejection rates in patients treated with both daclizumab and mycophenolate mofetil (plus standard cyclosporin-based immunosuppression) were lower than those achieved with mycophenolate mofetil alone. Preliminary results indicate that daclizumab is also a useful agent in paediatric renal transplant recipients. Further investigation of the efficacy and tolerability of the drug in this patient group is clearly warranted. Daclizumab does not increase the incidence of adverse events when added to standard cyclosporin-based therapy. The incidence of opportunistic infections, lymphoproliferative disorders and malignancies was not increased above that seen with placebo. CONCLUSIONS: Although the effects of daclizumab on long term graft and patient survival require further investigation, available data indicate that daclizumab is an important advance in renal transplant immunosuppression, reducing acute graft rejection without affecting the tolerability of standard cyclosporin-based immunosuppression.     

Population pharmacokinetic analysis of tacrolimus in Mexican paediatric renal transplant patients: role of CYP3A5 genotype and formulation

Aims

The aims of this study were (i) to develop a population pharmacokinetic (PK) model of tacrolimus in a Mexican renal transplant paediatric population (n = 53) and (ii) to test the influence of different covariates on its PK properties to facilitate dose individualization.

Methods

Population PK and variability parameters were estimated from whole blood drug concentration profiles obtained at steady-state using the non-linear mixed effect modelling software NONMEM® Version 7.2.

Results

Tacrolimus PK profiles exhibited high inter-patient variability (IPV). A two compartment model with first order input and elimination described the tacrolimus PK profiles in the studied population. The relationship between CYP3A5 genotype and tacrolimus CL/F was included in the final model. CL/F in CYP3A5*1/*1 and *1/*3 carriers was approximately 2- and 1.5-fold higher than in CYP3A5*3/*3 carriers (non-expressers), respectively, and explained almost the entire IPV in CL/F. Other covariates retained in the final model were the tacrolimus dose and formulation type. Limustin® showed markedly lower concentrations than the rest of the formulations.

Conclusions

Population PK modelling of tacrolimus in paediatric renal transplant recipients identified the tacrolimus formulation type as a significant covariate affecting the blood concentrations and confirmed the previously reported significant effect of CYP3A5 genotype on CL/F. It allowed the design of a proposed dosage based on the final model that is expected to help to improve tacrolimus dosing.     

肾移植病人中CYP3A4基因多态性对环孢素A代谢的影响

目的 用基因分析技术对CsA代谢酶CYP3A4进行基因分型,以阐述CYP3A4基因多态性对环孢素A代谢的影响及相互关系,从而预测血药浓度及安全性。方法 用聚合酶链反应结合限制性片段长度多态性分析法分别建立了CYP3A的CYP3A4基因亚型3个新突变点(CYP3A4~*4,~*5,~*6)的基因分型方法,并对中国肾移植人群进行基因分型,同时测定CsA及其代谢物浓度,以原形药与代谢物浓度的比值MR作为表型验证指标。结果CYP3A4~*4,*~5,*~6等位基因在中国肾移植人群中的突变率为:2/133,3/197,3/200。野生型病人中肝肾功能正常和异常者测得MR均值分别为0.47±0.13和0.82±0.21。3种突变型病人MR均值为0.90±0.30。结论CYP3A4~*4,~*5,~*6等位基因的存在有可能降低了药物代谢酶CYP3A4的活性,从而使环孢素A的代谢减慢。     

肝移植患者他克莫司血药浓度与细胞色素P450 3A5 1*3基因多态性的关系

目的研究细胞色素P450 3A5 1*3基因多态性对肝移植患者他克莫司(免疫抑制剂)血药浓度的影响,探讨他克莫司在不同个体间吸收、代谢差异的基因背景。方法观察150例肝移植术后常规使用他克莫司 吗替麦考酚酯胶囊 醋酸泼尼松三联免疫抑制治疗的成年患者,分别测定术后1、3、6个月和12月的他克莫司全血药浓度,采用等位基因特异PCR测定细胞色素P450 3A5 1*3基因多态性,比较不同基因型之间他克莫司的浓度/剂量比的差异。结果在口服相同剂量的他克莫司时,1个月内CYP3A5 1*1、CYP3A5 1*3和CYP3A5 3*3三种基因型的浓度/剂量比,差异不显著;但3个月后,差异显著;6个月和12个月的浓度/剂量比,差异非常显著。结论CYP3A5 1*3多态性与肝移植患者他克莫司血药浓度具有非常显著的相关性,携带等位基因1*1和1*3患者的血药浓度明显低于3*3纯合子患者。     

回顾性研究细胞色素P4503A5基因多态性对肾移植病人环孢素浓度的影响

目的 回顾性研究稳定期肾移植的病人在合用地尔硫卓后,CYP3A5基因多态性对环孢素(免疫抑制剂)浓度的影响.方法 用RFLP-PCR检测CYP3A5基因型;采用回顾性研究方法,分析肾移植病人CYP3A5基因型与环孢素血药浓度的关系.结果 合用地尔硫卓的病人,按CYP3A5不同基因型分组,3组病人之间的环孢素剂量和剂量调整浓度有明显差异;而不用地尔硫卓的病人进行分组后,环孢素剂量调整浓度也存在显著差异;环孢素剂量调整浓度,CYP3A5表达者显著低于不表达者组.结论 CYP3A5基因型对稳定期肾移植病人环孢素药代动力学有显著影响,且此相关性不受合用地尔硫卓影响.     

Tacrolimus dose requirement in renal transplant recipients is significantly higher when used in combination with corticosteroids

AIMS: To evaluate the effect of corticosteroids on tacrolimus pharmacokinetics. METHODS: In a randomized trial, kidney transplant recipients were treated with tacrolimus and mycophenolate mofetil with either daclizumab (n = 31) or 3 months of prednisone (n = 34). Tacrolimus dose-adjusted predose concentrations (C0) at month 1-6 were compared between both groups and within the corticosteroid group before and after prednisone withdrawal. RESULTS: At month 1 the tacrolimus dose-adjusted C0 in the corticosteroid group was 83 +/- 8 vs 119 +/- 17 ng ml-1 mg-1 kg-1 in the daclizumab group. The tacrolimus dose-adjusted C0 within the corticosteroid group at month 1 and 2 was 42% and 29% lower compared with month 4 (P < 0.001). CONCLUSIONS: A higher tacrolimus dose is required to reach target concentrations when used in combination with corticosteroids.