European Journal of Clinical Pharmacology

, Volume 66, Issue 11, pp 1119–1130 | Cite as

Effects of uridine diphosphate glucuronosyltransferase 2B7 and 1A7 pharmacogenomics and patient clinical parameters on steady-state mycophenolic acid pharmacokinetics in glomerulonephritis

  • Melanie S. Joy
  • Tammy Boyette
  • Yichun Hu
  • Jinzhao Wang
  • Mary La
  • Susan L. Hogan
  • Paul W. Stewart
  • Ronald J. Falk
  • Mary Anne Dooley
  • Philip C. Smith
Pharmacogenetics

Abstract

Purpose

The role of pharmacogenomics, clinical and demographic parameters in pharmacokinetic predictions was evaluated in patients receiving mycophenolic acid (MPA).

Methods

A cohort study design of patients with glomerulonephritis secondary to lupus nephritis and anti-neutrophil cytoplasmic antibody (ANCA) vasculitis was employed. Forty-six patients with lupus nephritis and ANCA vasculitis who were receiving MPA were recruited from the nephrology clinic. The study assessed the relative single and combined roles of genomic, clinical, and demographic characteristics on pharmacokinetic parameters using general linear models. The study focused on polymorphisms in UGT1A7, UGT2B7, and ABCB1/MDR1; all of which have limited data available concerning MPA pharmacokinetics. All patients had pharmacokinetic assessments for MPA and glucuronide metabolites (MPAG, AcMPAG). Genotyping was performed for known variants of UGTs (UGT1A9, UGT1A7, UGT2B7), and multidrug resistance protein (ABCB1/MDR1), involved in MPA disposition. Analyses included univariate and multivariate linear modeling.

Results

In univariate analyses, UGT2B7 heterozygosity (coefficient 0.3508; R 2=0.0873) and UGT1A7 heterozygosity (coefficient 0.3778; R 2=0.0966) predicted increased apparent oral clearance of MPA. UGT1A7 heterozygosity (coefficient −0.4647; R 2 0.0897) predicted lower MPA trough concentrations. In multivariate assessments, higher urinary protein excretion, lower serum creatinine, and increased weight predicted greater apparent oral clearance of MPA (p < 0.0001). White race and higher serum creatinine predicted higher MPA trough concentrations (p < 0.0001). Higher exposure to MPA was predicted by decreased urinary protein excretion and increased serum creatinine.

Conclusions

Clinical and demographic parameters were 2–4 times more important in MPA disposition than genotypes and explained 30–40% of the pharmacokinetic parameters.

Keywords

Mycophenolic acid UGT2B7 UGT1A7 ABCB1 MDR1 Glomerulonephritis 

Notes

Acknowledgement

We wish to thank Howard McLeod, PharmD for review of and suggestions for this manuscript. This research was funded by the National Institutes of Health 5K23DK64888, General Clinical Research Centers program of the Division of Research Resources, National Institutes of Health RR00046, Clinical and Translational Science Award U54RR024383, and the American College of Clinical Pharmacy Research Institute’s Frontier’s Award.

References

  1. 1.
    Shipkova M, Strassburg CP, Braun F, Streit F, Gröne HJ, Armstrong VW, Tukey RH, Oellerich M, Wieland E (2001) Glucuronide and glucoside conjugation of mycophenolic acid by human liver, kidney and intestinal microsomes. Br J Pharmacol 132:1027–1034CrossRefPubMedGoogle Scholar
  2. 2.
    Fisher MB, Paine MF, Strelevitz TJ, Wrighton SA (2001) The role of hepatic and extrahepatic UDP-glucuronosyltransferases in human drug metabolism. Drug Metab Rev 33:273–297CrossRefPubMedGoogle Scholar
  3. 3.
    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 81:392–400CrossRefPubMedGoogle Scholar
  4. 4.
    Levesque E, Benoit-Biancamano MO, Delage R, Couture F, Guillemette C (2008) Pharmacokinetics of mycophenolate mofetil and its glucuronide metabolites in healthy volunteers. Pharmacogenomics 9:869–879CrossRefPubMedGoogle Scholar
  5. 5.
    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 34:1539–1545CrossRefPubMedGoogle Scholar
  6. 6.
    Inoue K, Miura M, Satoh S, Kagaya H, Saito M, Habuchi T, Suzuki T (2007) Influence of UGT1A7 and UGT1A9 intronic I399 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Ther Drug Monit 29:299–304CrossRefPubMedGoogle Scholar
  7. 7.
    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 63:279–288CrossRefPubMedGoogle Scholar
  8. 8.
    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-2152 T on early mycophenolic acid dose-interval exposure in de novo renal allograft recipients. Clin Pharmacol Ther 78:351–361CrossRefPubMedGoogle Scholar
  9. 9.
    Zhang WX, Chen B, Jin Z, Yu Z, Wang X, Chen H, Mao A, Cai W (2008) Influence of uridine diphosphate (UDP)-glucuronosyltransferases and ABCC2 genetic polymorphisms on the pharmacokinetics of mycophenolic acid and its metabolites in Chinese renal transplant recipients. Xenobiotica 38:1422–1436CrossRefPubMedGoogle Scholar
  10. 10.
    Miura M, Satoh S, Inoue K, Kagaya H, Saito M, Inoue T, Suzuki T, Habuchi T (2007) Influence of SLCO1B1, 1B3, 2B1 and ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Eur J Clin Pharmacol 63:1161–1169CrossRefPubMedGoogle Scholar
  11. 11.
    Wang J, Figurski M, Shaw LM, Burckart GJ (2008) The impact of P-glycoprotein and Mrp2 on mycophenolic acid levels in mice. Transpl Immunol 19:192–196CrossRefPubMedGoogle Scholar
  12. 12.
    Miura M, Satoh S, Inoue K, Kagaya H, Saito M, Suzuki T, Habuchi T (2008) Influence of lansoprazole and rabeprazole on mycophenolic acid pharmacokinetics one year after renal transplantation. Ther Drug Monit 30:46–51CrossRefPubMedGoogle Scholar
  13. 13.
    Joy MS, Hilliard T, Hu Y, Hogan SL, Dooley MA, Falk RJ, Smith PC (2009) Pharmacokinetics of mycophenolic acid in patients with lupus nephritis. Pharmacotherapy 29:7–16CrossRefPubMedGoogle Scholar
  14. 14.
    Joy MS, Hilliard T, Yichun H, Hogan SL, Wang J, Falk RJ, Smith PC (2009) Influence of clinical and demographic variables on mycophenolic acid pharmacokinetics in anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis. Ann Pharmacother 43:1020–1027CrossRefPubMedGoogle Scholar
  15. 15.
    Wiwattanawongsa K, Heinzen EL, Kemp DC, Dupuis RE, Smith PC (2001) Determination of mycophenolic acid and its phenol glucuronide metabolite in human plasma and urine by high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 763:35–45CrossRefPubMedGoogle Scholar
  16. 16.
    Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41CrossRefPubMedGoogle Scholar
  17. 17.
    Bullingham RE, Nicholls AJ, Kamm BR (1998) Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 34:429–455CrossRefPubMedGoogle Scholar
  18. 18.
    Staatz CE, Tett SE (2007) Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients. Clin Pharmacokinet 46:13–58CrossRefPubMedGoogle Scholar
  19. 19.
    Nolin TD, Naud J, Leblond FA, Pichette V (2008) Emerging evidence of the impact of kidney disease on drug metabolism and transport. Clin Pharmacol Ther 83:898–903CrossRefPubMedGoogle Scholar
  20. 20.
    Joy MS, Gipson DS, Dike M, Powell L, Thompson A, Vento S, Eddy A, Fogo AB, Kopp JB, Cattran D, Trachtman H. (2009) Phase I trial of rosiglitazone in FSGS. I. Report of the FONT Study Group. Clin J Am Soc Nephrol 4:39–47CrossRefPubMedGoogle Scholar
  21. 21.
    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 17:871–880CrossRefPubMedGoogle Scholar
  22. 22.
    Shaw LM, Korecka M, Aradhye S, Grossman R, Bayer L, Innes C, Cucciara A, Barker C, Naji A, Nicholls A, Brayman K (2000) Mycophenolic acid area under the curve values in African American and Caucasian renal transplant patients are comparable. J Clin Pharmacol 40:624–633CrossRefPubMedGoogle Scholar
  23. 23.
    Naesens M, Kuypers DR, Verbeke K, Vanrenterghem Y (2006) Multidrug resistance protein 2 genetic polymorphisms influence mycophenolic acid exposure in renal allograft recipients. Transplantation 82:1074–1084CrossRefPubMedGoogle Scholar
  24. 24.
    Suzuki T, Zhao YL, Nadai M, Naruhashi K, Shimizu A, Takagi K, Takagi K, Hasegawa T (2006) Gender-related differences in expression and function of hepatic P-glycoprotein and multidrug resistance-associated protein (Mrp2) in rats. Life Sci 79:455–461CrossRefPubMedGoogle Scholar
  25. 25.
    Rost D, Kopplow K, Gehrke S, Mueller S, Friess H, Ittrich C, Mayer D, Stiehl A (2005) Gender-specific expression of liver organic anion transporters in rat. Eur J Clin Invest 35:635–643CrossRefPubMedGoogle Scholar
  26. 26.
    Baldelli S, Merlini S, Perico N, Nicastri A, Cortinovis M, Gotti E, Remuzzi G, Cattaneo D (2007) C-440 T/T-331C polymorphisms in the UGT1A9 gene affect the pharmacokinetics of mycophenolic acid in kidney transplantation. Pharmacogenomics 8:1127–1141CrossRefPubMedGoogle Scholar
  27. 27.
    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 32:775–778CrossRefPubMedGoogle Scholar
  28. 28.
    Basu NK, Kole L, Kubota S, Owens IS (2004) Human UDP-glucuronosyltransferases show atypical metabolism of mycophenolic acid and inhibition by curcumin. Drug Metab Dispos 32:768–773CrossRefPubMedGoogle Scholar
  29. 29.
    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 33:139–146CrossRefPubMedGoogle Scholar
  30. 30.
    Knights KM, Miners JO (2010) Renal UDP-glucuronosyltransferases and the glucuronidation of xenobiotics and endogenous mediators. Drug Metab Rev 42:60–70CrossRefPubMedGoogle Scholar
  31. 31.
    Ohno S, Nakajin S (2009) Determination of mRNA expression of human UDP-glucuronosyltransferases and application for localization in various human tissues by real-time reverse transcriptase-polymerase chain reaction. Drug Metab Dispos 37:32–40CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Melanie S. Joy
    • 1
    • 2
    • 4
  • Tammy Boyette
    • 1
  • Yichun Hu
    • 1
  • Jinzhao Wang
    • 1
  • Mary La
    • 1
  • Susan L. Hogan
    • 1
  • Paul W. Stewart
    • 3
  • Ronald J. Falk
    • 1
  • Mary Anne Dooley
    • 1
  • Philip C. Smith
    • 2
  1. 1.School of Medicine, UNC Kidney CenterUniversity of North CarolinaChapel HillUSA
  2. 2.Eshelman School of PharmacyUniversity of North CarolinaChapel HillUSA
  3. 3.School of Public HealthUniversity of North CarolinaChapel HillUSA
  4. 4.Division of Nephrology and Hypertension, Kidney Center, School of MedicineUniversity of North CarolinaChapel HillUSA

Personalised recommendations