Skip to main content

Advertisement

SpringerLink
Log in

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

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Shaw LM, Korecka M, Venkataramanan R, Goldberg L, Bloob R, Brayman KL (2003) Mycophenolic acid pharmacodynamics and pharmacokinetics provide a basis for rational monitoring strategies. Am J Transplant 3:534–542

    Article  PubMed  CAS  Google Scholar 

  2. Bullingham RE, Nicholls AJ, Kamm BR (1998) Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 34:429–455

    Article  PubMed  CAS  Google Scholar 

  3. Hale MD, Nicholls AJ, Bullingham RE, Hene R, Hoitsma A, Squifflet JP, Weimar W, Vanrenterghem Y, Van de Woude FJ, Verpooten GA (1998) The pharmacokinetic-pharmacodynamic relationship for mycophenolate mofetil in renal transplantation. Clin Pharmacol Ther 64:672–683

    Article  PubMed  CAS  Google Scholar 

  4. Mourad M, Malaise J, Chaib Eddour D, De Meyer M, Konig J, Schepers R, Squifflet JP, Wallemacq P (2001) Correlation of mycophenolic acid pharmacokinetic parameters with side effects in kidney transplant patients treated with mycophenolate mofetil. Clin Chem 47:88–94

    PubMed  CAS  Google Scholar 

  5. van Gelder T, Le Meur Y, Shaw LM, Oellerich M, DeNofrio D, Holt C, Holt DW, Kaplan B, Kuypers D, Meiser B, Toenshoff B, Mamelok RD (2006) Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 28:145–154

    Article  PubMed  CAS  Google Scholar 

  6. van Hest RM, Hesselink DA, Vulto AG, Mathot RA, van Gelder T (2006) Individualization of mycophenolate mofetil dose in renal transplant recipients. Expert Opin Pharmacother 7:361–376

    Article  PubMed  Google Scholar 

  7. Naesens M, Kuypers DR, Verbeke K, Vanrenterghem Y (2006) Multidrug resistance protein 2 genetic polymorphisms influence mycophenolic acid exposure in renal allograft recipients. Transplantation 82:1074–1084

    Article  PubMed  CAS  Google Scholar 

  8. Hesselink DA, van Gelder T (2005) Genetic and nongenetic determinants of between-patient variability in the pharmacokinetics of mycophenolic acid. Clin Pharmacol Ther 78:317–321

    Article  PubMed  CAS  Google Scholar 

  9. Strassburg CP, Oldhafer K, Manns MP, Tukey RH (1997) Differential expression of the UGT1A locus in human liver, biliary, and gastric tissue: Identification of UGT1A7 and UGT1A10 transcripts in extrahepatic tissue. Mol Pharmacol 52:212–220

    PubMed  CAS  Google Scholar 

  10. Bowalgaha K, Miners JO (2001) The glucuronidation of mycophenolic acid by human liver, kidney and jejunum microsomes. Br J Clin Pharmacol 52:605–609

    Article  PubMed  CAS  Google Scholar 

  11. Strassburg CP, Manns MP, Tukey RH (1998) Expression of the UDP-glucuronosyltransferase 1A locus in human colon identification and characterization of the novel extrahepatic UGT1A8. J Biol Chem 273:8719–8726

    Article  PubMed  CAS  Google Scholar 

  12. Tukey RH, Strassburg CP (2000) Human UDP-glucuronosyltransferases: Metabolism, expression, and disease. Annu Rev Pharmacol Toxicol 40:581–616

    Article  PubMed  CAS  Google Scholar 

  13. Cheng Z, Radominska-Pandya A, Tephly TR (1998) Cloning and expression of human UDP-glucuronosyltransferase (UGT) 1A8. Arch Biochem Biophys 356:301–305

    Article  PubMed  CAS  Google Scholar 

  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 14:501–515

    Article  PubMed  CAS  Google Scholar 

  15. Bernard O, Guillemette C (2004) The main role of UGT1A9 in the hepatic metabolism of mycophenolic acid and the effects of naturally occurring variants. Drug Metab Dispos 32:775–778

    Article  PubMed  CAS  Google 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 78:351–361

    Article  PubMed  CAS  Google Scholar 

  17. Huang YH, Galijatovic A, Nguyen N, Geske D, Beaton D, Green J, Green M, Peters WH, Tukey RH (2002) Identification and functional characterization of UDP-glucuronosyltransferases UGT1A8*1, UGT1A8*2 and UGT1A8*3. Pharmacogenetics 12:287–297

    Article  PubMed  CAS  Google 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 34:1539–1545

    Google Scholar 

  19. Jacobson PA, Green KG, Hering BJ (2005) Mycophenolate mofetil in islet cell transplant: Variable pharmacokinetics but good correlation between total and unbound concentrations. J Clin Pharmacol 45:901–909

    Article  PubMed  CAS  Google Scholar 

  20. Argikar UA, Cloyd JC, Birnbaum AK, Leppik IE, Conway J, Kshirsagar S, Oetting WS, Klein EC, Remmel RP (2006) Paradoxical urinary phenytoin metabolite (S)/R) ratios in CYP2C19*1/*2 patients. Epilepsy Res 71:54–63

    Article  PubMed  CAS  Google Scholar 

  21. Kagaya H, Inoue K, Miura M, Satoh S, Saito M, Tada H, Habuchi T, Suzuki T (2007) Influence of UGT1A8 and UGT2B7 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Eur J Clin Pharmacol 63:279–288

    Article  PubMed  CAS  Google 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 81:392–400

    Article  PubMed  CAS  Google 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 6:63–75

    Article  PubMed  CAS  Google 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 5:225–232

    Article  PubMed  CAS  Google Scholar 

  25. Vidal E, Cantarell C, Capdevila L, Monforte V, Roman A, Pou L (2000) Mycophenolate mofetil pharmacokinetics in transplant patients receiving cyclosporine or tacrolimus in combination therapy. Pharmacol Toxicol 87:182–184

    Article  PubMed  CAS  Google Scholar 

  26. Zucker K, Tsaroucha A, Olson L, Esquenazi V, Tzakis A, Miller J (1999) Evidence that tacrolimus augments the bioavailability of mycophenolate mofetil through the inhibition of mycophenolic acid glucuronidation. Ther Drug Monit 21:35–43

    Article  PubMed  CAS  Google 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 29:334–336

    Article  PubMed  CAS  Google 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 29:275–280

    Article  PubMed  CAS  Google Scholar 

  29. Hesselink DA, van Hest RM, Mathot RA, Bonthuis F, Weimar W, de Bruin RW, van Gelder T (2005) Cyclosporine interacts with mycophenolic acid by inhibiting the multidrug resistance-associated protein 2. Am J Transplant 5:987–994

    Article  PubMed  CAS  Google Scholar 

  30. Kumar V, Locuson CW, Sham YY, Tracy TS (2006) Amiodarone analog-dependent effects on CYP2C9-mediated metabolism and kinetic profiles. Drug Metab Dispos 34:1688–1696

    Article  PubMed  CAS  Google Scholar 

  31. Picard N, Djebli N, Sauvage FL, Marquet P (2007) Metabolism of sirolimus in the presence or absence of cyclosporine by genotyped human liver microsomes and recombinant cytochromes P450 3A4 and 3A5. Drug Metab Dispos 35:350–355

    Article  PubMed  CAS  Google Scholar 

  32. Djebli N, Picard N, Rerolle JP, Le Meur Y, Marquet P (2007) Influence of the UGT2B7 promoter region and exon 2 polymorphisms and comedications on acyl-MPAG production in vitro and in adult renal transplant patients. Pharmacogenet Genomics 17:321–330

    Article  PubMed  CAS  Google 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 43:866–880

    Article  PubMed  CAS  Google 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 17:871–880

    Article  PubMed  CAS  Google 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 6:121–128

    Article  PubMed  CAS  Google Scholar 

  36. Picard N, Ratanasavanh D, Premaud A, Le Meur Y, Marquet P (2005) Identification of the UDP-glucuronosyltransferase isoforms involved in mycophenolic acid phase II metabolism. Drug Metab Dispos 33:139–146

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This project was supported by NIAID U19 AI070119 (PJ, WO, SB, AM), T32 CA099936, and the Children’s Cancer Research Fund (LJ). Dr. Jacobson has received financial support from Roche Pharmaceuticals. No financial support was received from Roche for this project.

Author information

Authors and Affiliations

  1. Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, 55455, USA

    L’Aurelle A. Johnson

  2. Department of Experimental and Clinical Pharmacology and Human Genetics, University of Minnesota, Minneapolis, MN, 55455, USA

    William S. Oetting

  3. Department of Biostatistics, University of Minnesota, Minneapolis, MN, 55455, USA

    Saonli Basu

  4. College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA

    Susie Prausa

  5. Department of Surgery, University of Minnesota, Minneapolis, MN, 55455, USA

    Arthur Matas

  6. Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Weaver Densford Hall 7-151, 308 Harvard St. SE, Minneapolis, MN, 55455, USA

    Pamala A. Jacobson

Authors
  1. L’Aurelle A. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William S. Oetting
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Saonli Basu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Susie Prausa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Arthur Matas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pamala A. Jacobson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pamala A. Jacobson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Johnson, L.A., Oetting, W.S., Basu, S. et al. Pharmacogenetic effect of the UGT polymorphisms on mycophenolate is modified by calcineurin inhibitors. Eur J Clin Pharmacol 64, 1047–1056 (2008). https://doi.org/10.1007/s00228-008-0501-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-008-0501-y

Keywords

Search

Navigation