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

doi:10.1016/j.transproceed.2005.01.077

Transplantation Proceedings

Volume 37, Issue 1, January–February 2005, Pages 178-181

https://doi.org/10.1016/j.transproceed.2005.01.077 Get rights and content

Abstract

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.

Section snippets

Materials and methods

All outpatient renal transplant recipients who had received a renal graft at least 1 year before the start of the study were eligible to participate. Unrelated Chinese renal transplant recipients (n = 167, 86 men and 81 women) were recruited and gave informed consent. A 5 mL sample of anticoagulated venous blood was obtained from each patient. DNA was extracted by a phenol/chloroform procedure.

CsA and tacrolimus doses and predose concentrations, as well as demographic and clinical data, were

Results

Among 167 renal transplant patients assessed for CYP3A5 genotype, 137 patients were treated with CsA and 30 patients were treated with tacrolimus. Of the 137 patients treated with CsA, one was a CYP3A5*6 allele carrier. We excluded this patient from further analysis. The majority of patients treated with CsA were homozygous for the CYP3A5*3 variant allele (n = 72, 53%). They were expected to lack CYP3A5 activity. Also, 54 patients (39.7%) carried 1 CYP3A5*1 allele and 10 patients (7.3%) had the

Discussion

The calcineurin inhibitors tacrolimus and CsA have been the cornerstone of immunosuppressive therapy in many types of allograft recipients. However, the bioavailability when administered orally is quite variable. This observation may be attributed to several factors including poor absorption or extensive first-pass metabolism in the intestine and liver. Tacrolimus and CsA are substrates for CYP3A. CYP3A is the primary CYP subfamily in humans that is responsible for the phase I metabolism of

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Frequencies and Association of CYP3A5 Polymorphism With Tacrolimus Concentration Among Renal Transplant Recipients in Vietnam
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Citation Excerpt :
The highest frequency of CYP3A5*3 variant reported up to 93% in the European population, whereas the African population had the lowest allele frequency of 30% [12]. Our findings showed a high frequency of CYP3A5*3 allele variant that is similar with previous studies reported in Chinese, Korean, and Myanmar patients with the frequency of 71%, 78.6%, and 60.97%, respectively [14–16]. To our knowledge, there was only one report that investigated pharmacogenomics of CYP3A5 in the Vietnamese population [17].
This study aims to investigate the frequencies and association of CYP3A5 polymorphism with tacrolimus concentration among renal transplant recipients in Vietnam. Methods. Sixty-eight kidney transplant recipients were included in this study from the department of nephrology and dialysis, Military Hospital 103. Blood samples were collected for monitoring of tacrolimus levels and determination of CYP3A5 genetic polymorphism.
A total of 68 patients studied. The CYP3A5*3*3, CYP3A5*1*3, and CYP3A5*1*1 genotypes were detected in 48 (70.6%), 16 (23.5%), and 4 (5.9%), respectively. Tacrolimus concentrations were much lower in CYP3A5 expressors than in CYP3A5 nonexpressors on the first day, month 1, 3, 6, and 12 (5.98 ± 1.05 vs 6.57 ± 1.03, P = .03; 5.79 ± 1.13 vs 6.82 ± 1.05, P < .001; 4.76 ± 1.48 vs 6.73 ± 1.09, P < .001; 4.29 ± 1.64 vs 6.46 ± 1.23, P < .001; 4.20 ± 1.36 vs 6.04 ± 1.26, P < .001), respectively. Notably, the concentration/dose ratio in the CYP3A5 expressors was lower than in CYP3A5 nonexpressors at time points of follow up (P < .001). However, there were no significant differences in the age, sex, HLA mismatch, type of donors, acute rejection, and creatinine levels at time points between group of CYP3A5 expressors and those of CYP3A5 nonexpressors.
In conclusion, this research indicated the significant association of CYP3A5 genetic polymorphism with daily dose and tacrolimus concentrations in renal transplant recipients. This study provided a closer step to individualize the dose of tacrolimus in renal transplant patients in Vietnam.
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Genetic polymorphisms of CYP3A5 genes and concentration of the cyclosporine and tacrolimus

Abstract

Objective

Methods

Results

Conclusion

Section snippets

Materials and methods

Results

Discussion

Am J Kidney Dis

Clin Pharmacokinet

Am J Transplant

Am J Kidney Dis

Analysis of the risk factors of late failure in renal transplantation under cyclosporine immunosuppression

Transplant Proc

Pharmacokinetics and pharmacodynamics of FK506 in pediatric patients receiving living-related donor liver transplantations

Transplant Proc

Molecular and physical mechanisms of first-pass extraction

Drug Metab Dispos