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。     

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.     

The effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients

Cyclosporine and tacrolimus are immunosuppressive drugs largely used in renal transplantation. They are characterized by a wide inter-individual variability in their pharmacokinetics with a potential impact on their therapeutic efficacy or induced toxicity. CYP3A5 and P-glycoprotein appear as important determinants of the metabolism of these drugs. The objective of this study was to investigate the effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood concentrations in stable transplant patients. Stable renal transplant recipients receiving cyclosporine (n = 50) or tacrolimus (n = 50) were genotyped for CYP3A5*3 and *6, and MDR1 C1236T, G2677T/A and C3435T. Dose-adjusted trough blood levels (ng/ml per mg/kg body weight) as well as doses (mg/kg body weight) required to achieve target blood concentrations were compared among patients according to allelic status for CYP3A5 and MDR1. Dose-adjusted trough concentrations were three-fold and 1.6-fold higher in CYP3A5*3/*3 patients than in CYP3A5*1/*3 patients for tacrolimus and cyclosporine, respectively. In the case of tacrolimus, the difference was even more striking when considering CYP3A5*1/*1 patients showing dose-adjusted trough concentrations 5.8-fold lower than CYP3A5*3/*3 patients. For both drugs, no association was found between trough blood concentrations or dose requirement and MDR1 genotype. Multiple regression analyses showed that CYP3A5*1/*3 polymorphism explained up to 45% of the variability in dose requirement in relation to tacrolimus use. Given the importance of rapidly achieving target blood concentrations after transplantation, further prospective studies should consider the immediate post-graft period and assess the influence of this specific polymorphism. Beside non-genetic factors (e.g. steroids dosing, drugs interactions), CYP3A5 pharmacogenetic testing performed just before transplantation could contribute to a better individualization of immunosuppressive therapy.     

Effect of genetic polymorphisms of CYP3A5 and MDR1 on cyclosporine concentration during the early stage after renal transplantation in Chinese patients co-treated with diltiazem

Objective  The aim of this study was to assess the influence of the cytochrome (CYP450)3A5 and multidrug resistance (MDR1) gene polymorphisms on cyclosporine A (CsA) trough concentration during the early stage after renal transplantation in Chinese patients co-treated with diltiazem. Methods   CYP3A5*3 (A6986G) and MDR1 C1236T, G2677T/A and C3435T polymorphisms were determined by PCR followed by restriction fragment length polymorphism (RFLP) analysis. A total of 112 Chinese renal transplant patients were enrolled in the study. The whole blood trough concentration was measured at 7 days after transplantation, and the dose-adjusted trough levels were compared among the different genotypes. Results  The dose-adjusted trough levels of CsA were significantly higher in MDR1 2677TT carriers than in GG plus GT carriers (59.5 ± 15.9 vs. 34.5 ± 9.4 vs. 43.2 ± 13.6 ng/mL per mg per kg; P < 0.0001). In patients who were co-treated with diltiazem, compared with carriers of haplotype T-T-C, the carriers of haplotype C-G-C and haplotype T-G-T had significantly lower dose-adjusted trough blood concentrations of CsA than the non-carrier group (P = 0.002, P = 0.000 and P = 0.000, respectively). However, no evidence was found that there was a relationship between the CYP3A5*3, MDR1 C1236T and MDR1 C3435T polymorphisms and CsA dose-adjusted trough concentrations. Conclusion  This study demonstrated that the G2677T/A single nucleotide polymorphisms in MDR1 and MDR1 haplotypes C-G-C, T-G-T and T-T-C are associated with the CsA concentration during the very early post-transplant period in Chinese renal transplant patients co-treated with diltiazem. These polymorphisms may be useful for determining the appropriate initial dose of CsA after renal transplantation.     

Influence of rabeprazole and lansoprazole on the pharmacokinetics of tacrolimus in relation to CYP2C19, CYP3A5 and MDR1 polymorphisms in renal transplant recipients

The objective of this study was to evaluate whether genetic polymorphisms of CYP2C19, CYP3A5 and MDR1 significantly impact the interaction between tacrolimus and rabeprazole or lansoprazole. Seventy-three recipients were randomly assigned after renal transplantation to receive repeated doses of tacrolimus for 28 days with a regimen of either 20 mg of rabeprazole or 30 mg of lansoprazole. Blood concentrations of tacrolimus were measured by microparticle enzyme immunoassay. The mean daily dose and the dose-adjusted area under the plasma concentration-time curves from 0 to 12 h (AUC(0-12)) of tacrolimus coadministered with rabeprazole or lansoprazole were the lowest and highest, respectively, in CYP2C19 poor metabolizers (PMs) having the CYP3A5*3/*3 genotype (0.084 and 0.112 mg/kg/day and 1.269 and 1.033 ng.h/ml/mg/kg, respectively). On the other hand, the mean dose-adjusted AUC(0-12) of tacrolimus coadministered with rabeprazole or lansoprazole were the highest in CYP2C19 PMs having the MDR13435CC+CT genotype, but not significantly.The present study indicates that there are significant interactions between tacrolimus and rabeprazole or lansoprazole in CYP2C19 PM renal transplant recipients bearing the CYP3A5*3/*3 genotypes. For recipients having these genetic polymorphisms, lower dosages of tacrolimus are required to achieve the target therapeutic index.     

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.     

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.     

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。     

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.     

CYP3A4*18B基因多态性与他克莫司血药浓度的相关性研究

目的:探讨中国汉族肾移植患者CYP3A 4* 18B基因型对术后1个月内他克莫司谷浓度的影响.方法:采用限制性片段长度多态性技术分析了30例汉族患者CYP3A4* 18B基因型,采用酶增强免疫测定技术测定患者他克莫司谷浓度.将血药浓度标准化后对不同基因型患者剂量调整谷浓度差异进行t检验.结果:测得CY P3A 4*18B等位基因频率为0.333,符合Hardy-Weinberg平衡.将患者分成*1/*1型慢代谢组和*1/*18B合并*18B/*18B型快代谢组,两组标准化谷浓度分别为(98.02±18.56) ng·kg·mL-1· mg-1和(62.91±18.15) ng· kg· mL-1· mg-1 (P＜0.01),慢代谢组的FK506剂量调整谷浓度显著高于快代谢组.结论:CYP3A 4* 18B基因多态性与他克莫司剂量调整谷浓度显著相关,该突变可能导致CYP3A4酶活性的提高.     

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和MDR1基因型对尿毒症患者肾移植术后早期他克莫司血药浓度和肌酐水平的影响

目的 评价真实临床实践中CYP3A5(CYP3A5*3,6986A>G)及MDR1(C3435>T,G2677>T/A,C1236>T)基因多态性对尿毒症患者接受肾移植术后早期他克莫司血药浓度的影响及其最佳治疗浓度。方法 以入选2013～2017年单中心的131例首次肾移植术且术后以他克莫司为基础进行三联免疫治疗的患者为对象,开展回顾性研究,考察患者基因多态性对他克莫司的日剂量、血药浓度、血药浓度/剂量比值和肌酐水平的影响。结果 在维持他克莫司靶浓度（10～15 ng/ml）的前提下,肾移植术后4周内基因型为CYP3A5*3/*3(GG)肾移植受者的给药剂量低于基因型CYP3A5*1/*1(AA)和CYP3A5*1/*3(AG)。患者血药浓度在10～13 ng/ml内时,其血肌酐水平最接近正常值。结论 CYP3A5基因多态性影响肾移植受者他克莫司的血药浓度,未发现MDR1基因多态性对他克莫司血药浓度的影响。早期肾移植血药浓度控制在10～13 ng/ml时,患者移植肾功能最接近正常人肾功能水平。     

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。     

Influence of lansoprazole and rabeprazole on mycophenolic acid pharmacokinetics one year after renal transplantation

Peptic ulcer disease is a common complication after organ transplantation, and long-term administration of antiulcer agents is needed in many renal transplant recipients. Although several drug interactions with mycophenolic acid (MPA), the active metabolite of the prodrug mycophenolate mofetil (MMF), have been reported, little is known about the interaction between MPA and proton pump inhibitors (PPIs). The present study investigated the drug interaction between MMF and lansoprazole or rabeprazole and the impact of cytochrome (CYP) 2C19, and multidrug resistance (MDR)1 C3435T polymorphisms on these drug interactions at 1 year after renal transplantation. Retrospectively, 61 recipients were divided into 3 groups: MMF and tacrolimus as combination immunosuppressive therapy, together with either 30 mg lansoprazole (n = 22) or 10 mg rabeprazole (n = 17), or without PPI (n = 22). One year after transplantation, plasma concentrations of MPA were measured by high-performance liquid chromatography. The mean dose-unadjusted and -adjusted Cmax of MPA with 30 mg lansoprazole were significantly lower than those without PPI (11.8 vs. 17.8 microg/mL, P = 0.0197, and 22.6 vs. 33.1 ng/mL/mg MMF, P = 0.0222, respectively). In recipients having the CYP2C19 *1/*2+*1/*3 or MDR1 C3435T CC genotype, the mean dose-adjusted AUC0-12 of MPA with 30 mg lansoprazole was significantly smaller than that with 10 mg rabeprazole or without PPI. The plasma concentration of MPA was influenced by 30 mg lansoprazole but not 10 mg rabeprazole. Because of the greater gastric acid secretion-inhibitory effect of 30 mg lansoprazole in recipients having the CYP2C19 *1/*2+*1/*3 (intermediate metabolizer) or MDR1 C3435T CC genotype, the elution and hydrolysis of MMF might be decreased. Although the clinical relevance might be minor, the fact that administration of 30 mg lansoprazole in patients having the CYP2C19 *2 or *3 allele or the MDR1 C3435T CC genotype diminishes the absorption of MPA in the maintenance stage after renal transplantation should be taken into consideration with regard to the MPA pharmacokinetics.     

Minimal effect of MDR1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of indinavir in HIV-infected patients

AIMS: The protease inhibitor indinavir is characterized by an important interindividual pharmacokinetic variability, which results from the actions of the metabolizing enzymes cytochrome P450 (CYP) 3A and the multidrug efflux pump P-glycoprotein (P-gp), encoded by MDR1. Using a population pharmacokinetic approach, we investigated the effect of several MDR1 and CYP3A5 polymorphisms on the pharmacokinetic parameters of indinavir in HIV-infected patients. METHODS: Twenty-eight patients receiving indinavir alone or together with ritonavir were included. Indinavir pharmacokinetics were studied over a 12 h interval. Genetic polymorphisms were assessed by real-time PCR assays and direct sequencing for MDR1 and by PCR-SSCP analysis for CYP3A5. RESULTS: The pharmacokinetics of indinavir were best described by a one-compartment model with first-order absorption. In the final model, the MDR1 C3435T genotype and ritonavir were identified as statistically significant covariates (P 相似文献   

Herbal medicine yin zhi huang induces CYP3A4-mediated sulfoxidation and CYP2C19-dependent hydroxylation of omeprazole

Aim： To explore the potential interactions between Y/n Zhi Huang （YZH） and omeprazole, a substrate of CYP3A4 and CYP2C19. Methods： Eighteen healthy volunteers, including 6 CYP2C19＊ 1/＊ 1, 6 CYP2C19＊1/＊2 or ＊3 and 6 CYP2C19＊2/ ＊2 were enrolled in a 2-phase, randomized, crossover clinical trial. In each phase, the volunteers received either placebo or 10 mL YZH oral liquid, 3 times daily for 14 d. Then all the patients took a 20 mg omeprazole capsule orally. Blood samples were collected up to 12 h after omeprazole administration. Plasma concentrations of omeprazole and its metabolites were quantified by HPLC with UV detection. Results： After 14 d of treatment of YZH, plasma omeprazole significantly decreased and those of omeprazole sulfone and 5-hydroxyomeprazole significantly increased. The ratios of the area under the plasma concentration-time curves from time 0 to infinity （AUC（0-∞） of omeprazole to 5-hydroxyomprazole and those of omeprazole to omeprazole sulfone decreased by 64.80%＋ 12.51% （P= 0.001） and 63.31%＋ 18.45 % （P=0.004） in CYP2C 19＊ 1/＊ 1, 57.98 %± 14.80% （P=0.002） and 54.87%±18.42% （P=0.003） in CYP2C19＊1/＊2 or ＊3, and 37.74%±16.07% （P= 0.004） and 45.16%±15.54% （P=0.003） in CYP2C19＊2/＊2, respectively. The decrease of the AUC（0-∞） ratio of omeprazole to 5-hydroxyomprazole in CYP2C19＊ 1/＊ 1 and CYP2C19＊1/＊2 or ＊3 was greater than those in CYP2C19＊2/＊2 （P=0.047 and P=0.009）. Conclusion： YZH induces both CYP3A4-catalyzed sulfoxidation and CYP2C19-dependent hydroxylation of omeprazole leading to decreases in plasma omeprazole concentrations.     

Association of CYP3A4*18B polymorphisms with the pharmacokinetics of cyclosporine in healthy subjects

The aim of this study is to evaluate the association of the CYP3A4*18B genotype with the cyclosporine metabolism in healthy subjects. We employed PCR–RFLP assays for analysis of the CYP3A4*18B genotype. Each of 26 subjects, comprising 12 CYP3A4*1/*1, 12 CYP3A4*1/*18B and 2 CYP3A4*18B/*18B, was given a single oral dose of cyclosporine (4?mg?kg^?1). The plasma concentrations of cyclosporine were measured for up to 24?h post dose by high-performance liquid chromatography–electrospray mass spectrometry. We found that the mean C_max (95% confidence intervals) of cyclosporine were 2237 (2905, 1859) (*1/*1), 2247 (2916, 1869) (*1/*18B), and 905 (1192, 506) ng?ml^?1 (*18B/*18B) (p?=?0.037) and the mean AUC0-4 were 5026 (6181, 4372) (*1/*1), 4434 (5481, 3841) (*1/*18B) and 2561 (3155, 1736) ng ml-1?h (*18B/*18B) (p?=?0.021). The CL in the *18B/*18B group was significantly higher than in the *1/*1 group. However, T_max exhibited no difference among the three genotypes. *18B/*18B group showed 50% reduction in concentration at 2?h post dose compared with *1/*18B (p?=?0.062) or *1/*1 (p?=?0.047), but no statistical significance was detected between*1/*1 and *1/*18B groups (p?>?0.05). The data suggest that the CYP3A4*18B genotype affects cyclosporine pharmacokinetics probably resulting from a higher enzymatic activity of this mutation in healthy subjects.     

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。     

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.