Elsevier

Transplantation Proceedings

Volume 41, Issue 6, July–August 2009, Pages 2313-2316
Transplantation Proceedings

Immunosuppression
Agent
The Prevalence of Uridine Diphosphate-Glucuronosyltransferase 1A9 (UGT1A9) Gene Promoter Region Single-Nucleotide Polymorphisms T-275A and C-2152T and Its Influence on Mycophenolic Acid Pharmacokinetics in Stable Renal Transplant Patients

https://doi.org/10.1016/j.transproceed.2009.06.038Get rights and content

Abstract

The aim of this study was to evaluate the distribution of UGT1A9 promoter region T-275A and C-2152T single nucleotide polymorphisms (SNPs) in stable transplant patients and to investigate the impact of these SNPs on mycophenolic acid (MPA) pharmacokinetics.

Methods

In total, 133 Caucasian renal transplant recipients were studied. Also a complete 12-hour pharmacokinetic profile was recorded for 15 transplant patients who had the polymorphism and for 15 controls who were randomly chosen since they received the same type and dosage of mycophenolate, same posttransplant time and similar renal function.

Results

The T-275A promoter mutation was detected in 12.03% of patients and the C-2152T in 9.77%. All patients with the mutation C-2152T had associated the mutation T-275A. Patients who carried either the T-275A or the C-2152T polymorphism (or both) experienced more admissions owing to gastrointestinal side effects (P < .05). The pharmacokinetics studies showed that carriers of T-275A and/or C-2152T displayed a smaller area under-concentration time curve (AUC): 57.8 ± 4.3 vs 78.9 ± 10.8 mg/Lh (P < .03).

Conclusion

It seemed that carriers of T-275A and C-2152T SNPs of the UGT1A9 gene promoter region in the late posttransplant recipient group, showed a greater incidence of gastrointestinal side effects and a lower MPA exposure.

Section snippets

Patients and Methods

We studied 133 Caucasian renal transplant recipients using 12-hour pharmacokinetic profiles including 15 transplant patients who showed the polymorphism and 15 transplant controls who were randomly chosen based on treatment with the same type and dosage of mycophenolate, same posttransplant time, and similar renal function. All patients who participated in the pharmacokinetic study were treated with tacrolimus.

Before blood sample collection, there had been no mycophenolate dose change for at

Results

The T-275A promoter mutation was detected in 12.03% of the patients and the C-2152T in 9.77%. All patients with the mutation C-2152T had associated the mutation T-275A. Patients who carried either the T-275A or the C-2152T polymorphism (or both) had more admissions due to gastrointestinal side effects (P < .05). The review of the patient medical histories showed a greater incidence and severity of gastrointestinal side effects in the patients with SNPs.

Pharmacokinetics studies showed that

Discussion

UGT1A9 is the key UGT responsible for glucuronidation of MPA to its inactive 7-O-glucuronide (MPAG). It is predominantly active in the liver, kidney, and intestine.13 We have evaluated the impact of specific SNPs of the UGT1A9 gene that resulted in increased in vitro glucuronidation activity (T-275A and C-2152T) and decreased enzymatic activity (UGT1A93 mutation).

The prevalences of T-275A and C-2152T SNPs of the UGT1A9 gene promoter region were similar to those previously described in the

References (13)

  • H. de Jonge et al.

    Pharmacogenetics in solid organ transplantation: current status and future directions

    Transplant Rev (Orlando)

    (2008)
  • T. van Gelder et al.

    Therapeutic drug monitoring of mycophenolate mofetil in transplantation

    Ther Drug Monit

    (2006)
  • L.M. Shaw et al.

    Current issues in therapeutic drug monitoring of mycophenolic acid: report of a roundtable discussion

    Ther Drug Monit

    (2001)
  • R. Borrows et al.

    Determinants of mycophenolic acid levels after renal transplantation

    Ther Drug Monit

    (2005)
  • M.D. Hale et al.

    The pharmacokinetic-pharmacodynamic relationship for mycophenolate mofetil in renal transplantation

    Clin Pharmacol Ther

    (1998)
  • W.E. Evans et al.

    Pharmacogenomics, drug disposition, drug targets, and side effects

    N Engl J Med

    (2003)
There are more references available in the full text version of this article.

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