Pharmacogenetic effect of the UGT polymorphisms on mycophenolate is modified by calcineurin inhibitors
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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.
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.
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.
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.
KeywordsKidney transplantation Mycophenolate Pharmacogenetics Polymorphisms Uridine diphosphate-glucuronosyltransferase
- 14.Girard H, Court MH, Bernard O, Fortier LC, Villeneuve L, Hao Q, Greenblatt DJ, von Moltke LL, Perussed L, Guillemette C (2004) Identification of common polymorphisms in the promoter of the UGT1A9 gene: Evidence that UGT1A9 protein and activity levels are strongly genetically controlled in the liver. Pharmacogenetics 14:501–515PubMedCrossRefGoogle Scholar
- 16.Kuypers DR, Naesens M, Vermeire S, Vanrenterghem Y (2005) The impact of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) gene promoter region single-nucleotide polymorphisms T-275A and C-2152T on early mycophenolic acid dose-interval exposure in de novo renal allograft recipients. Clin Pharmacol Ther 78:351–361PubMedCrossRefGoogle Scholar
- 18.Bernard O, Tojcic J, Journault K, Perusse L, Guillemette C (2006) Influence of nonsynonymous polymorphisms of UGT1A8 and UGT2B7 metabolizing enzymes on the formation of phenolic and acyl glucuronides of mycophenolic acid. Drug Metab Dispos 34:1539–1545Google Scholar
- 22.Levesque E, Delage R, Benoit-Biancamano MO, Caron P, Bernard O, Couture F, Guillemette C (2007) The impact of UGT1A8, UGT1A9, and UGT2B7 genetic polymorphisms on the pharmacokinetic profile of mycophenolic acid after a single oral dose in healthy volunteers. Clin Pharmacol Ther 81:392–400PubMedCrossRefGoogle Scholar
- 23.Saeki M, Saito Y, Jinno H, Sai K, Ozawa S, Kurose K, Kaniwa N, Komamura K, Kotake T, Morishita H, Kamakura S, Kitakaze M, Tomoike H, Shirao K, Tamura T, Yamamoto N, Kunitoh H, Hamaguchi T, Yoshida T, Kubota K, Ohtsu A, Muto M, Minami H, Saijo N, Kamatani N, Sawada JI (2006) Haplotype structures of the UGT1A gene complex in a Japanese population. Pharmacogenomics J 6:63–75PubMedCrossRefGoogle Scholar
- 24.Zucker K, Rosen A, Tsaroucha A, de Faria L, Roth D, Ciancio G, Esquenazi V, Burke G, Tzakis A, Miller J (1997) Unexpected augmentation of mycophenolic acid pharmacokinetics in renal transplant patients receiving tacrolimus and mycophenolate mofetil in combination therapy, and analogous in vitro findings. Transpl Immunol 5:225–232PubMedCrossRefGoogle Scholar
- 27.Zucker K, Rosen A, Tsaroucha A, de Faria L, Roth D, Ciancio G, Esquenazi V, Burke G, Tzakis A, Miller J (1997) Augmentation of mycophenolate mofetil pharmacokinetics in renal transplant patients receiving prograf and CellCept in combination therapy. Transplant Proc 29:334–336PubMedCrossRefGoogle Scholar
- 28.Naito T, Shinno K, Maeda T, Kagawa Y, Hashimoto H, Otsuka A, Takayama T, Ushiyama T, Suzuki K, Ozono S (2006) Effects of calcineurin inhibitors on pharmacokinetics of mycophenolic acid and its glucuronide metabolite during the maintenance period following renal transplantation. Biol Pharm Bull 29:275–280PubMedCrossRefGoogle Scholar
- 33.Kuypers DR, Claes K, Evenepoel P, Maes B, Coosemans W, Pirenne J, Vanrenterghem Y (2003) Long-term changes in mycophenolic acid exposure in combination with tacrolimus and corticosteroids are dose dependent and not reflected by trough plasma concentration: A prospective study in 100 de novo renal allograft recipients. J Clin Pharmacol 43:866–880PubMedCrossRefGoogle Scholar
- 34.van Hest RM, Mathot RA, Pescovitz MD, Gordon R, Mamelok RD, van Gelder T (2006) Explaining variability in mycophenolic acid exposure to optimize mycophenolate mofetil dosing: A population pharmacokinetic meta-analysis of mycophenolic acid in renal transplant recipients. J Am Soc Nephrol 17:871–880PubMedCrossRefGoogle Scholar
- 35.Borrows R, Chusney G, Loucaidou M, James A, Lee J, Tromp JV, Owen J, Cairns T, Griffith M, Hakim N, McLean A, Palmer A, Papalois V, Taube D (2006) Mycophenolic acid 12-h trough level monitoring in renal transplantation: Association with acute rejection and toxicity. Am J Transplant 6:121–128PubMedCrossRefGoogle Scholar