Multidrug resistance gene-1 (MDR-1) haplotypes have a minor influence on tacrolimus dose requirements

P-glycoprotein (P-gp) and the drug metabolizing enzymes have major pharmacokinetic effects. Variability in tacrolimus absorption is influenced by P-gp activity which, in turn, is affected by single nucleotide polymorphisms (SNPs) within the multidrug resistance-1 gene (MDR-1). Tacrolimus dose requirements of 206 stable renal transplant patients were related to MDR-1 genotypes of SNPs C1236T, G2677T/A and C3435T, as well as haplotypes: C-G-C and T-T-T. Lower dose-normalized blood tacrolimus concentrations were achieved for: 2677-GG genotype patients, as compared to 2677-TT, and for 3435-CC patients as compared to 3435-TT patients. There was a small, but significant, difference in dose requirements between haplotypes C-G-C and T-T-T patients, which was not significant when patients were subclassified as producers and non-producers of cytochrome P450 3A5 (CYP3A5). The activities of CYP3A5 and P-gp have been shown to influence bioavailability of several drugs. Our data suggest that MDR-1 haplotypes have a relatively minor association with tacrolimus pharmacokinetics.     

Significant impact of gene polymorphisms on tacrolimus but not cyclosporine dosing in Asian renal transplant recipients

Calcineurin inhibitors (CNI) are metabolized by cytochrome-P4503A (CYP3A) enzymes and extruded into the intestinal lumen by the drug efflux pump, P-glycoprotein (P-gp). The impact of single nucleotide polymorphisms (SNPs) of genes encoding CYP3A5 and P-gp on CNI dosing was examined among Asian renal transplant recipients. Frequencies of CYP3A5*1 versus *3 and MDR1-C3435T were correlated with tacrolimus (TAC) and cyclosporine (CSA) concentration-to-dose (C/D) ratios. Among 82 recipients (49% male; 88% Chinese), the majority were CYP3A5 expressors (*1*1 and *1*3, 11% and 40%, respectively) and 49% were nonexpressors (*3/*3). The prevalence of MDR-1-C3435T variants was 3435CC (41%), 3435CT (46%), and 3435TT (13%). Among 18 TAC-treated recipients, all receiving Diltiazem (DTZ), the median C/D ratio was lower for CYP3A5 *1/*1 versus *1/*3 versus *3/*3 (1.9, 4.6, and 13.5 ng/mL per 0.1 mg/kg/d, respectively; P = .001). The median C/D ratio was higher for TAC-treated patients with MDR-1-3435CC (14.1, 7.3, and 2.2 ng/mL per 0.1 mg/kg/d for CC, CT, and TT, respectively; P = .023). Neither CYP3A5 nor MDR-1-C3435T variants had an impact on CSA C/D ratios. Thus, CYP3A5 SNP has a significant impact on TAC dosing in Asian renal transplant recipients, which was likely to facilitate TAC metabolism. Although MDR-1-3435CC with higher P-gp expression should experience more TAC efflux and, therefore, lower TAC C/D ratios, all MDR-1-3435CC carriers were CYP3A5 nonexpressors; the latter ultimately contributed to the observed higher TAC C/D ratios in this population. This study advocates starting with a higher TAC dose for CYP3A5 expressors. Coadministration of DTZ may further optimize the TAC level through preferential P-gp binding and CYP3A4 inhibition.     

Impact of cytochrome P450 3A and ATP-binding cassette subfamily B member 1 polymorphisms on tacrolimus dose-adjusted trough concentrations among Korean renal transplant recipients

Background

Tacrolimus is a substrate of cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp), encoded by the CYP3A and ATP-binding cassette subfamily B member 1 (ABCB1) genes, respectively. This study was aimed to investigate the impact of CYP3A and ABCB1 polymorphisms on the tacrolimus pharmacokinetics and clinical outcomes in Korean renal transplant recipients.

Methods

We analyzed data from a cohort of 70 renal transplant recipients receiving tacrolimus. CYP3A4*4, CYP3A4*5, CYP3A4*18, CYP3A5*3, ABCB1 C1236>T, ABCB1 G2677>T/A, and ABCB1 C3435>T polymorphisms were genotyped and correlated to dose-adjusted tacrolimus trough concentration at months 1, 3, 6, and 12 after transplantation.

Results

Patients with the CYP3A5*3 alleles showed higher dose-adjusted tacrolimus concentrations for 12 months and higher trough levels until 6 months after transplantation. ABCB1 polymorphisms and haplotypes were not associated with tacrolimus concentrations. In a multivariate analysis, the presence of ≥1 CYP3A5*3 allele was a significant independent variable affecting dose-adjusted tacrolimus concentrations. Glomerular filtration rate, acute rejection, opportunistic infection, and graft survival were not affected by CYP3A5 polymorphisms. Calcineurin inhibitor toxicity, which showed higher tendency in patients with CYP3A5*1 alleles, might be associated with higher tacrolimus dose per kilogram.

Conclusions

The CYP3A5 genotype is a major factor in determining the dose requirement of tacrolimus, and genotyping may be of value in individualization of immunosuppressive therapy of renal transplant patients.     

CYP3A5 and ABCB1 Polymorphisms and Tacrolimus Pharmacokinetics in Renal Transplant Candidates: Guidelines from an Experimental Study

Genetic polymorphisms in biotransformation enzyme CYP3A5 (6986G > A, CYP3A5*3; 14690A > G, CYP3A5*6) and drug transporter ABCB1 (1236C > T; 2677G > T/A; 3435C > T) are known to influence tacrolimus (Tac) dose requirements and trough blood levels in stable transplant patients. In a group of 19 volunteers selected with relevant genotypes among a list of 221 adult renal transplant candidates, we evaluated whether consideration of CYP3A5 and ABCB1 genetic polymorphisms could explain the interindividual variability in Tac pharmacokinetics after the first administration of a standard dose (0.1 mg/kg body weight twice a day). Lower area under the time versus blood concentration curves (AUC) or lower trough concentrations were observed among CYP3A5 expressors (n = 9) than among nonexpressors (n = 10) using two different analytical methods for Tac determination (liquid chromatography with tandem mass spectrometry (LC-MS/MS) and immunoassay). The median AUC(0-infinity) was 2.6- and 2.1-fold higher in nonexpressors for LC-MS/MS and immunologic methods, respectively. No difference was observed in Tac pharmacokinetic parameters in relation to ABCB1 polymorphisms. In conclusion, our study confirms the very significant effect of CYP3A5 polymorphism early after the first administration of Tac. It also provides a strong argument for a doubling of the loading dose in patients early identified a priori on the transplantation list as possessing at least one CYP3A5*1 allele.     

Tacrolimus dose requirement in relation to donor and recipient ABCB1 and CYP3A5 gene polymorphisms in Chinese liver transplant patients.

The aim of this study was to investigate whether the heterogeneity in tacrolimus dose requirement is associated with ABCB1 and CYP3A5 gene polymorphisms in Chinese liver transplant patients during the first month after transplantation. ABCB1 and CYP3A5 genotyping was performed using the polymerase chain reaction restriction sites polymorphism-based procedure in Chinese liver transplant recipients (n = 50) and their corresponding donors (n = 50). Tacrolimus whole-blood trough concentrations were measured by immunoassays on the IMx analyzers (Abbott Diagnostics Laboratories, Abbott-Park, IL). Doses required to achieve target blood concentrations and dose-adjusted trough concentrations (concentration/dose [C/D] ratios) were compared among patients according to allelic status of ABCB1 and CYP3A5. The ABCB1 3435CC was observed in 23 subjects (23%), whereas 64 (64%) carried 3435CT and 13 (13%) carried 3435TT. The CYP3A5*1/*1 was observed in 13 subjects (13%), 50 (50%) carried *1/*3, and 37 (37%) carried*3/*3. The tacrolimus C/D ratios were obviously lower in recipients carrying ABCB1 3435CC genotype. For CYP3A5, recipients who received organs from CYP3A5*3/*3 donors had higher C/D ratios. But the donors' ABCB1 and recipients' CYP3A5 genotype did not affect the recipients' pharmacokinetics. Analysis of the combination of recipients' ABCB1 and donors' CYP3A5 genotypes revealed that the tacrolimus C/D ratios were significantly lower in the ABCB1 3435CC-carrying recipients, regardless of donors' CYP3A5 genotype. In conclusion, our finding suggests that the recipients' ABCB1 and donors' CYP3A5 genotype affect the tacrolimus dose requirements. ABCB1 C3435T polymorphism is a major determinant of tacrolimus trough concentration in Chinese liver transplant recipients, and recipients with 3435CC genotype will require higher dose of tacrolimus.     

Tacrolimus Dosing in Pediatric Heart Transplant Patients is Related to CYP3A5 and MDR1 Gene Polymorphisms

Tacrolimus is a substrate for P-glycoprotein (P-gp) and cytochrome (CYP) P4503A. P-gp is encoded by the multiple drug resistance gene MDR1 and CYP3A is the major enzyme responsible for tacrolimus metabolism. Both MDR1 and CYP3A5 genes have multiple single nucleotide polymorphisms. The objective of this study was to evaluate whether the MDR1 exon21 and exon26 polymorphisms and the CYP3A5 polymorphism are associated with tacrolimus disposition in pediatric heart transplant patients. At 3, 6 and 12 months post transplantation, a significant difference in tacrolimus blood level per dose/kg/day was found between the CYP3A5 *1/*3 (CYP3A5 expressor) vs. *3/*3 (nonexpressor) genotypes with the *1/*3 patients requiring a larger tacrolimus dose to maintain the same blood concentration. There were no significant differences in tacrolimus blood level per dose/kg/day between MDR1 exon21 G2677T and exon 26 C3435T at 3 months, but both were found to have a significant association with tacrolimus blood level per dose/kg/day at 6 and 12 months. We conclude that specific genotypes of MDR1 and CYP3A5 in pediatric heart transplant patients require larger tacrolimus doses to maintain their tacrolimus blood concentration, and that this information could be used prospectively to manage patient's immunosuppressive therapy.     

Influence of CYP3A5 and MDR1 polymorphisms on tacrolimus concentration in the early stage after renal transplantation

OBJECTIVE: Tacrolimus is an immunosuppressive drug with a narrow therapeutic range and wide interindividual variation in its pharmacokinetics. Cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp, encoded by MDR1) play an important role in the absorption and metabolism of tacrolimus. The objective of this study was to evaluate whether or not CYP3A5*1/*3 or MDR1 C3435T polymorphisms are associated with the tacrolimus concentration per dose. METHODS: CYP3A5 and MDR1 genotypes were determined by polymerase chain reaction followed by restriction fragment length polymorphism analysis in 118 Chinese renal transplant patients receiving tacrolimus. Whole blood trough tacrolimus concentration was measured by enzyme-linked immunosorbent assay and dose-adjusted concentration (ng/mL per mg/kg/d) was calculated at 1 wk, 1 month, and 3 months after transplantation. RESULTS: The dose-adjusted concentration of CYP3A5*1/*1 and *1/*3 patients was significantly lower than *3/*3 patients (32.8 +/- 17.7 and 41.6 +/- 15.8 vs. 102.3 +/- 51.2 at 1 wk; 33.1 +/- 7.5 and 46.4 +/- 12.9 vs. 103 +/- 47.5 at 1 month; 35.3 +/- 20.9 and 59.0 +/- 20.6 vs. 150 +/- 85.3 at 3 months after transplantation respectively). At 1 wk, 46% of the CYP3A5*1 allele carriers had a tacrolimus concentration lower than 5 ng/mL and 77% lower than 8 ng/mL, whereas 20% of the *3/*3 patients had a concentration higher than 20 ng/mL. There was a mild difference between *1/*1 homozygotes and *1/*3 heterozygotes at 1 and 3 months after transplantation. No difference was found among the MDR1 genotypes. CONCLUSION: CYP3A5*1/*3 polymorphisms are associated with tacrolimus pharmacokinetics and dose requirements in renal transplant recipients. Pharmacogenetic methods could be employed prospectively to help initial dose selection and to individualize immunosuppressive therapy.     

Impact of CYP3A5 and MDR1(ABCB1) C3435T polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients

OBJECTIVE: The objective of this study was to assess the influence of CYP3A5 and MDR1 genetic polymorphisms on tacrolimus pharmacokinetics in Japanese renal transplant recipients. METHOD: The pharmacokinetic parameters of tacrolimus were calculated in steady-state on day 28 after transplantation. Polymerase chain reaction-restriction fragment length polymorphism and direct sequence methods were used for CYP3A5 and MDR1 polymorphisms, respectively. RESULTS: The dose-adjusted area under the concentration-time curve (AUC0-12) was significantly lower among CYP3A5*1 carriers than those bearing CYP3A5*3/*3. (0.570 +/- 0.105 vs 0.865 +/- 0.343 ng.h/mL per mg/kg, P = .00322). The daily tacrolimus dose per body weight was significantly higher in CYP3A5*1 carriers than those of CYP3A5*3/*3 carriers (0.271 +/- 0.110 vs 0.150 +/- 0.056 mg/kg, P = .00016). In this study, a distinction was made between carriers of CYP3A5*1/*1+*1/*3 and CYP3A5*3/*3 to investigate the influence of the MDR1 C3435T mutation on tacrolimus pharmacokinetics. The MDR1 C3435T polymorphisms did not affect any tacrolimus pharmacokinetic parameter in either group. CONCLUSIONS: Renal transplant recipients who were CYP3A5*1 carriers required a higher dose of tacrolimus than CYP3A5*3/*3, indicating a significantly lower dose-adjusted AUC0-12 of tacrolimus. In contrast, MDR1 C3435T polymorphism was not an important factor in tacrolimus pharmacokinetics.     

Genetic polymorphisms and individualized tacrolimus dosing

Background

Genetic polymorphisms of metabolism enzymes or intestinal drug transporters may affect pharmacokinetic responses to immunosuppressive drugs in renal transplant recipients. We sought to identify the frequency of genetic polymorphisms and their importance for individualization of tacrolimus doses.

Patients and Methods

We performed an observational study in 35 renal transplant recipients treated with tacrolimus, mycophenolate mofetil, and corticosteroids. Tacrolimus concentrations were determined by immunoanalysis (IMx method; Abbott Diagnostics, Abbott Park, Ill), on 11 blood samples per patient during the first 6 weeks after renal transplantation. For each patient, we calculated the mean value and its standard error (SEM) of the concentration/dose ratio (ng/mL/mg) of tacrolimus. The pharmacogenetic analysis included single nucleotide polymorphisms (SNPs) in the CYP3A5 (CYP3A5*3 (A6986G), CYP3A5*6 (G14690A), MDR1 (C3435T and G2677T/A) and PXR (C-25385T) genes.

Results

Of the patients, 62.8% (n = 22) were men and the overall mean age was 55 years (95% confidence interval, 48.7-62.7). The SNP distribution was: CYP3A5*3: G/G = 82.9%, A/G = 17.1%; CYP3A5*6: G/G = 88.6%, G/A = 11.4%; MDR1 C3435T: C/C = 25.7%, C/T = 62.9%, T/T = 11.4%; for MDR1 G2677T/A: G/G = 22.9%, G/T = 65.7%, T/T = 11.4% and for PXR: C/T = 85.7%, T/T = 14.3%. Tacrolimus concentration/dose ratios in heterozygote patients for CYP3A5*3 genotypes was >120% lower than for the homozygote CYP3A5*3 genotype (0.65 ± 0.04 vs 1.45 ± 0.05; P < .0001). Wild-type MDR1 (3435 C/C) genotype patients showed up to 40% lower concentration/dose ratios compared with heterozygote and homozygote genotypes (C/C; 1 ± 0.07 vs C/T; 1.4 ± 0.06 vs T/T; 1.37 ± 0.09; P < .0001).

Conclusion

Intestinal absorption and metabolism of tacrolimus was significantly affected by the SNPs in the CYP3A5 and MDR1 genes, which may offer a useful tool to optimize tacrolimus dosing after renal transplantation.     

Impact of ABCB1 (MDR1) haplotypes on tacrolimus dosing in adult lung transplant patients who are CYP3A5 *3/*3 non-expressors

BACKGROUND: The influence of ABCB1 (MDR1) polymorphisms on tacrolimus dosing has been questioned in previous studies with contradictory findings, possibly due to the association between CYP3A5 polymorphisms and tacrolimus dosing. The objective of this study was to assess the effect of ABCB1 haplotypes from 3 distinct polymorphic sites on the tacrolimus level/dose [L/D] in lung transplant patients limited to CYP3A5 *3/*3 non-expressors. METHOD: A total of 91 lung transplant patients treated primarily with tacrolimus and prednisone were enrolled, and clinical information on drug dosing and blood levels was collected. The [L/D] was calculated for patients receiving tacrolimus at 1, 3, 6, 9 and 12 months post transplant. ABCB1 polymorphisms at C1236T, G2677T, and C3435T were assessed by PCR amplification and DNA sequencing. Haplotypes were estimated by Arlequin ver.2.00. Haplotype effects on tacrolimus [L/D] were assessed by two-way ANOVA. RESULTS: Of the 10 haplotypes, CGC, TTT and CGT accounted for 44.1%, 40.7% and 7.6% of the total haplotypes, respectively. The tacrolimus [L/D] value in the CGC-CGC patients was significantly lower than in patients with CGC-TTT and TTT-TTT genotypes at the first month (mean [L/D]=1.45 versus 3.10 and 3.97 ngxmL(-)(1) /mg/day), and throughout the first post transplant year. CONCLUSION: This study demonstrates that ABCB1 haplotypes derived from three common polymorphisms are associated with tacrolimus dosing in lung transplant patients when eliminating the confounder CYP3A5 genotype.     

Association of CYP3A5, CYP2C8, and ABCB1 Polymorphisms With Early Renal Injury in Chinese Liver Transplant Recipients Receiving Tacrolimus

Background

The purpose of this study is to explore the association of CYP3A5, ABCB1, and CYP2C8 polymorphisms with the risk of developing early kidney impairment in Chinese liver transplant recipients receiving tacrolimus.

Influence of CYP3A5 and MDR1(ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in Chinese renal transplant recipients

The aims of this study were to investigate the influence of CYP3A5 and MDR1 genetic polymorphisms on tacrolimus pharmacokinetics in Chinese renal transplant recipients, so as to help rational administration in clinical practice. We calculated pharmacokinetic parameters of tacrolimus from blood concentrations in steady state at day 28. Polymerase chain reaction restriction fragment length polymorphisms were used for CYP3A5 and MDR1 analysis. The results showed that the dose-adjusted area under the concentration time curve (AUC_0-12) and renal clearance showed a significant difference between CYP3A5*1 carriers and the CYP3A5*3/*3 genotype (P < .01). In the following study, a distinction was made between carriers of CYP3A5*1/ vs CYP3A5*3/*3 seeking to investigate the influence of the MDR13435T>C polymorphism on tacrolimus pharmacokinetics. MDR1 3435T>C polymorphism did not affect any tacrolimus pharmacokinetic parameter in either group. Renal transplant recipients who were CYP3A5*1 carriers required a higher dose of tacrolimus than CYP3A5*3/*3, indicating a significantly lower dose-adjusted AUC_0-12 of tacrolimus. In contrast, MDR1 3435T>C polymorphism was not an important factor in tacrolimus pharmacokinetics. Pharmacogenetic methods may be used prospectively to aid dose selection and individualize immunosuppressive therapy.     

Genetic polymorphisms of CYP3A5 genes and concentration of the cyclosporine and tacrolimus

OBJECTIVE: CYP3A is the major enzyme responsible for metabolism of the calcineurin inhibitors cyclosporine (CsA) and tacrolimus. Our objective was to determine the relationship between genetic polymorphisms of CYP3A5 with respect to interindividual variability in CsA and tacrolimus pharmacokinetics. METHODS: Kidney transplant recipients receiving CsA (n = 137) or tacrolimus (n = 30) were genotyped for CYP3A5*3 and *6 by a PCR/RFLP method. The patients were grouped according to the CYP3A5 genotype. Dose-adjusted trough levels were correlated with the corresponding genotype. RESULTS: At 3, 6, and 12 months, the tacrolimus dose-adjusted trough levels (dose-adjusted C0) showed a statistically significant difference between the group of CYP3A5*3/*3 (n = 19) and the group of CYP3A5*1 allele carriers. The former was higher than the latter. The CsA dose-adjusted C0 and the actual C0 did not display a significant relation (P < .05) between the group of CYP3A5*3/*3 and the group of CYP3A5*1 allele carriers. CONCLUSION: Patients with the CYP3A5*3/*3 genotype require less tacrolimus to reach target concentrations compared to those with the CYP3A5*1 allele.     

肾移植术后他克莫司神经毒性与CYP3A5基因多态性的相关性研究

目的 总结CYP3A5基因多态性检测与肾移植患者术后他克莫司神经系统毒性的相关性.方法 回顾性分析我院2017年至2020年116例肾移植术后应用他克莫司的患者.采用DNA直接测序法检测患者CYP3A5基因多态性,观察不同基因的患者术后不同时间段的他克莫司药物浓度及神经毒性反应.结果 肾移植术后使用他克莫司的患者神经毒...     

Influence of CYP3A5 and MDR1 (ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients

BACKGROUND: A body-weight-based dose of tacrolimus often results in marked individual diversity of blood drug concentration. Tacrolimus is a substrate for cytochrome P450 (CYP) 3A5 and p-glycoprotein encoded by CYP3A5 and MDR1 (ABCB1), respectively, having multiple single nucleotide polymorphisms. In this study, we genotyped CYP3A5 A6986G, MDR1 G2677(A/T), and C3435T polymorphisms and investigated the association between these polymorphisms and the pharmacokinetics of tacrolimus in renal transplant recipients. METHODS: Thirty consecutive recipients were enrolled in this study. The pharmacokinetics of tacrolimus was analyzed on day 28 after transplant, when the daily dose was adjusted to the target trough level of 10-15 ng/mL. The polymerase chain reaction-restriction fragment length polymorphism and direct sequence method were used for genotyping the CYP3A5 and MDR1 polymorphisms, respectively. RESULTS: The single tacrolimus dose per body weight was significantly higher in CYP3A5 *1 carriers than CYP3A5 *3/*3 carriers (0.143+/-0.050 vs. 0.078+/-0.031 mg/kg, P<0.001). The dose-adjusted trough level and the area under the concentration-time curve (AUC0-12) were significantly lower in CYP3A5 *1 carriers than CYP3A5 *3/*3 carriers (0.040+/-0.014 vs. 0.057+/-0.024 ng/mL/mg/kg, P=0.015 and 0.583+/-0.162 vs. 0.899+/-0.319 ng.hr/mL/mg/kg, P=0.004), respectively. The MDR1 polymorphism was not associated with any pharmacokinetic parameters. CONCLUSIONS: Kidney transplant recipients with the CYP3A5 *1 allele required a higher daily tacrolimus dose compared with those with the CYP3A5 *3/*3 genotype to maintain both the target trough level and AUC0-12, suggesting that this polymorphism is useful for determining the appropriate dose of tacrolimus.     

The influence of CYP3A gene polymorphisms on cyclosporine dose requirement in renal allograft recipients

Cyclosporine is a substrate of cytochrome P-450 3A (CYP3A) subfamily of enzymes and characterized by a narrow therapeutic range with wide interindividual variation in pharmacokinetics. A few single-nucleotide polymorphisms detected in CYP3A genes have been shown to correlate significantly with the CYP3A protein expression and activity. We therefore postulated that these polymorphisms could be responsible for some of the interindividual variation in cyclosporine pharmacokinetics. The objective of our study is to determine correlation if any between single-nucleotide polymorphisms of CYP3A5 and CYP3AP1 on cyclosporine dose requirement and concentration-to-dose ratio in renal allograft recipients. Cyclosporine-dependent renal allograft recipients were genotyped for CYP3A5 A6986G and CYP3AP1 G-44A. The cyclosporine dosages prescribed and the corresponding cyclosporine trough levels for each patient were recorded so that cyclosporine dose per weight (mg/kg/day) and concentration-to-dose ratio (C(0)/D, whereby C(0) is trough level and D is daily dose per weight) could be calculated. A total of 67 patients were recruited for our study. The dose requirement for 1, 3, and 6 months post-transplantation ranged 2.3-11.4, 1.0-9.0, and 1.4-7.2 mg/kg/day, respectively. Patients with *1*1*1*1 (n=5) CYP3A5- and CYP3AP1-linked genotypes needed higher dose of cyclosporine compared to patients with *1*3*1*3 (n = 27) and *3*3*3*3 (n = 33) linked genotypes in months 3 and 6 post-transplantation (P < 0.016). The identification of patients with *1*1*1*1 by CYP3A5 and CYP3AP1 genotyping may have a clinically significant and positive impact on patient outcome with reduced rejection rate by providing pretransplant pharmacogenetic information for optimization of cyclosporine A dosing.     

Tacrolimus pharmacogenetics: the CYP3A5*1 allele predicts low dose-normalized tacrolimus blood concentrations in whites and South Asians

Previously, we demonstrated that the dose-normalized tacrolimus blood concentration after renal transplantation was associated with a single nucleotide polymorphism (SNP) in the CYP3AP1 gene, probably through linkage with an SNP in the CYP3A5 gene. Individuals with at least one CYP3A5*1 allele synthesize CYP3A5 and CYP3A5*3/*3 homozygotes do not. We now present results with direct typing of the CYP3A5 genotype for this group of 180 kidney-only transplant recipients from a single center. South Asian and white patients with at least one CYP3A5*1 allele achieved twofold lower dose-normalized tacrolimus blood concentrations compared with CYP3A5*3/*3 homozygotes, confirming our previous findings for the CYP3AP1 SNP. There was a significant delay in achieving target blood concentrations in those with at least one CYP3A5*1 allele. Determination of the CYP3A5*1/*3 genotype could be used to predict the tacrolimus dose requirement and, given incomplete linkage, would be better than determination of the CYP3AP1 genotype.     

CYP3A5基因型对肾移植受者术后早期血他克莫司浓度的影响

目的 探讨不同CYP3A5基因型对肾移植受者术后早期他克莫司(Tac)初始剂量的选择及其对血Tac目标浓度的影响.方法以新接受亲属活体肾移植的受者为研究对象,患者均应用Tac、霉酚酸酯(MMF)和泼尼松(Pred)预防排斥反应.研究分为2个阶段,第一阶段为同定剂量组(n=28),无论其CYP3A5分型如何,Tac的初始剂量均为1 mg·kg~(-1)·d~(-1);第二阶段为调整剂量组(n=40),CYP3A5表达者(仅包括*1/*3型,*1/*1型予以剔除)的Tac初始剂量为0.15mg·kg~(-1)·d~(-1),CYP3A5非表达者(*3/*3型)的初始剂量为0.08 mg·kg~(-1)·d~(-1).于术后3、5、7和14 d采集受者血样,检测血Tac浓度,有效的血Tac浓度以剂量校正的浓度比值(C/D)表示.结果固定剂量组28例受者中,CYP3A5*1/*3型15例,*3/*3型13例;调整剂量组40例受者中,CYP=3A5*l/*3型16例、*3/*3型24例.两组中,CYP3A5 *1/*3型受者术后3、5、7和14 d的血Tac浓度均低于*3/*3型受者,差异均有统计学意义(P<0.01).术后第3天,固定剂量组*1/*3型受者和*3/*3型受者达到目标血药浓度者分别占46.7%(7/15)和46.2%(6/13),调整剂量组*1/*3型受者和*3/*3型受者达到目标血药浓度者分别占81.2%(13/16)和75.0%(18/24),调整剂量组达到开标血药浓度者的百分率显著高于同定剂量组(P相似文献   

Effect of CYP3A5 Genotype on Renal Allograft Recipients Treated With Tacrolimus

Objective

Tacrolimus concentrations are associated with CYP3A5 genotype. The purpose of this study was to evaluate the outcomes and drug concentrations/doses among a posttransplant population with various CYP3A5 genotypes within 12 months.

Methods

Sixty seven kidney recipients receiving immunosuppression with tacrolimus + mycophenolate mofetil + prednisolone were grouped according to their CYP3A5 genotypes (*1/*1; *1/*3; *3/*3). The initial dose of tacrolimus (0.15 mg/kg/d) was adjusted according to achieve a target therapeutic window. All patients underwent a protocol biopsy at 1 month posttransplantation. We assayed serum creatinine and tacrolimus blood trough concentrations to calculate the concentration per dosage during follow-up. We also investigated the incidence of acute rejection episodes and the nephrotoxicity of tacrolimus according to the renal biopsy.

Results

There was no significant difference among serum creatinine concentrations. Tracrolimus blood concentrations showed a significant difference at day 7 and 1 month with no significant difference at 3, 6, or 12 months among the three groups. The CYP3A5*3/*3 group showed the largest concentration per dosage (C/D) and CYP3A5*1/*1, the smallest C/D. There was a significant difference among the three groups. The occurrence of an acute rejection episode within 3 months showed a significant difference among the three groups but not from 3 to 12 months after transplantation. Nephrotoxicity was greatest among the CYP3A5*3/*3 group.

Conclusion

CYP3A5 influenced the blood concentrations of tacrolimus. Our study suggested to choose the initial dosage according to the CYP3A5 genotype to obtain a better outcome and reduce the incidences of acute rejection episodes and nephrotoxicity.     

Influence of CYP3A5 and ABCB1 gene polymorphisms on calcineurin inhibitor‐related neurotoxicity after hematopoietic stem cell transplantation

Yanagimachi M, Naruto T, Tanoshima R, Kato H, Yokosuka T, Kajiwara R, Fujii H, Tanaka F, Goto H, Yagihashi T, Kosaki K, Yokota S. Influence of CYP3A5 and ABCB1 gene polymorphisms on calcineurin inhibitor‐related neurotoxicity after hematopoietic stem cell transplantation.
Clin Transplant 2010: 24: 855–861. © 2009 John Wiley & Sons A/S. Abstract: Background: One severe side effect of calcineurin inhibitors (CNIs: such as cyclosporine [CsA] and tacrolimus [FK506]) is neurotoxicity. CNIs are substrates for CYP3A5 and P‐glycoprotein (P‐gp), encoded by ABCB1 gene. In the present study, we hypothesized that genetic variability in CYP3A5 and ABCB1 genes may be associated with CNI‐related neurotoxicity. Methods: The effects of the polymorphisms, such as CYP3A5 A6986G, ABCB1 C1236T, G2677T/A, and C3435T, associated with CNI‐related neurotoxicity were evaluated in 63 patients with hematopoietic stem cell transplantation. Results: Of the 63 cases, 15 cases developed CNI‐related neurotoxicity. In the CsA patient group (n = 30), age (p = 0.008), hypertension (p = 0.017), renal dysfunction (p < 0.001), ABCB1 C1236T (p < 0.001), and G2677T/A (p = 0.014) were associated with neurotoxicities. The CC genotype at ABCB1 C1236T was associated with it, but not significantly so (p = 0.07), adjusted for age, hypertension, and renal dysfunction. In the FK506 patient group (n = 33), CYP3A5 A6986G (p < 0.001), and ABCB1 C1236T (p = 0.002) were associated with neurotoxicity. At least one A allele at CYP3A5 A6986G (expressor genotype) was strongly associated with it according to logistic regression analysis (p = 0.01; OR, 8.5; 95% CI, 1.4–51.4). Conclusion: The polymorphisms in CYP3A5 and ABCB1 genes were associated with CNI‐related neurotoxicity. This outcome is probably because of CYP3A5 or P‐gp functions or metabolites of CNIs.