Pharmacogenetic effect of the UGT polymorphisms on mycophenolate is modified by calcineurin inhibitors

  • L’Aurelle A. Johnson
  • William S. Oetting
  • Saonli Basu
  • Susie Prausa
  • Arthur Matas
  • Pamala A. Jacobson
Pharmacogenetics

Abstract

Background

Mycophenolic acid (MPA) is glucuronidated primarily by uridine diphosphate glucuronosyltransferase enzymes (UGT) 1A9 and 1A8. These enzymes are highly polymorphic resulting in low activity and high expression phenotypes. We hypothesized that polymorphisms of UGT1A9 and 1A8 may alter MPA pharmacokinetics in kidney transplantation.

Methods

One hundred seventeen kidney (n = 93), pancreas (n = 11), or simultaneous kidney and pancreas (SPK) (n = 13) transplant recipients were studied for the effect of UGT1A9 and UGT1A8 polymorphisms on MPA dose-corrected trough concentrations. Individuals were genotyped for UGT1A8 and UGT1A9 polymorphisms (1A8*2, 1A8*3, 1A9*3, 1A9-275 and 1A9-2152). Linear regression was used to estimate the effect of UGT polymorphisms on the individual’s mean MPA dose-corrected trough concentration with and without stratification by calcineurin inhibitor. A multiple linear regression analysis was performed to assess the dependence between the average MPA dose-corrected trough concentration and age, gender, UGT genotype (1A8*2, 1A8*3, 1A9*3, 1A9-275, 1A9-2152), serum albumin, hemoglobin (Hgb), hematocrit (HCT), liver transaminases (AST, ALT), serum creatinine, and bilirubin.

Results

Mycophenolic acid dose-corrected trough concentrations were 60% higher in subjects heterozygous or homozygous for UGT1A8*2 than in those with the wild type (p = 0.02); however, this effect was dependent on concomitant calcineurin inhibitor. When subjects were stratified by calcineurin inhibitor status, the UGT1A8*2 effect was only apparent in the tacrolimus group (p < 0.01). Mycophenolic acid dose-corrected trough concentrations were 70% lower in carriers of the UGT1A9 -275T>A/-2152 C>T polymorphism who received cyclosporine (p < 0.01). There was no effect of the UGT1A9 -275T>A/-2152C>T polymorphism in the tacrolimus group.

Conclusions

The effect of UGT1A8 and UGT1A9 variants on MPA metabolism appears to be modified by concomitant calcineurin inhibitor therapy. Confirmatory in vivo and in vitro studies are needed.

Keywords

Kidney transplantation Mycophenolate Pharmacogenetics Polymorphisms Uridine diphosphate-glucuronosyltransferase 

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • L’Aurelle A. Johnson
    • 1
  • William S. Oetting
    • 2
  • Saonli Basu
    • 3
  • Susie Prausa
    • 4
  • Arthur Matas
    • 5
  • Pamala A. Jacobson
    • 6
  1. 1.Department of Experimental and Clinical PharmacologyUniversity of MinnesotaMinneapolisUSA
  2. 2.Department of Experimental and Clinical Pharmacology and Human GeneticsUniversity of MinnesotaMinneapolisUSA
  3. 3.Department of BiostatisticsUniversity of MinnesotaMinneapolisUSA
  4. 4.College of PharmacyUniversity of MinnesotaMinneapolisUSA
  5. 5.Department of SurgeryUniversity of MinnesotaMinneapolisUSA
  6. 6.Department of Experimental and Clinical Pharmacology, College of PharmacyUniversity of MinnesotaMinneapolisUSA

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