UGT genotype may contribute to adverse events following medication with mycophenolate mofetil in pediatric kidney transplant recipients

Clinical Pharmacology and Therapeutics

Volumn 85, Issue 5, 2009, Pages 495-500

  Prausa, S E ^a,b   Fukuda, T ^a,b   Maseck, D ^a,b   Curtsinger, K L ^a,b   Liu, C ^a,b   Zhang, K ^a,b   Nick, T G ^a,b   Sherbotie, J R ^c   Ellis, E N ^d   Goebel, J ^a,b   Vinks, A A ^a,b  

^a CINCINNATI CHILDREN'S HOSPITAL MEDICAL CENTER   (United States)

^b UNIVERSITY OF CINCINNATI   (United States)

^c UNIVERSITY OF UTAH SCHOOL OF MEDICINE   (United States)

^d UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GLUCURONOSYLTRANSFERASE; GLUCURONOSYLTRANSFERASE 1A8; GLUCURONOSYLTRANSFERASE 1A9; GLUCURONOSYLTRANSFERASE 2B7; MYCOPHENOLIC ACID 2 MORPHOLINOETHYL ESTER;

ADOLESCENT; AREA UNDER THE CURVE; ARTICLE; CHILD; CLINICAL ARTICLE; CONTROLLED STUDY; DIARRHEA; DNA EXTRACTION; DNA SEQUENCE; DRUG DOSE REDUCTION; DRUG ELIMINATION; DRUG EXPOSURE; DRUG METABOLISM; DRUG TOLERABILITY; DRUG WITHDRAWAL; FEMALE; GENE FREQUENCY; GENOTYPE; GRAFT RECIPIENT; HETEROZYGOSITY; HOMOZYGOSITY; HUMAN; KIDNEY GRAFT REJECTION; KIDNEY TRANSPLANTATION; LEUKOPENIA; MALE; PRESCHOOL CHILD; PRIORITY JOURNAL; RECOMMENDED DRUG DOSE; SCHOOL CHILD; SINGLE NUCLEOTIDE POLYMORPHISM; UNSPECIFIED SIDE EFFECT;

ADOLESCENT; CHILD; CHILD, PRESCHOOL; DIARRHEA; DOSE-RESPONSE RELATIONSHIP, DRUG; FEMALE; GLUCURONOSYLTRANSFERASE; HETEROZYGOTE; HOMOZYGOTE; HUMANS; IMMUNOSUPPRESSIVE AGENTS; KIDNEY TRANSPLANTATION; LEUKOPENIA; MALE; MYCOPHENOLIC ACID; PILOT PROJECTS; POLYMORPHISM, GENETIC;

EID: 67349213569     PISSN: 00099236     EISSN: 15326535     Source Type: Journal    
DOI: 10.1038/clpt.2009.3     Document Type: Article

References (26)

1. Bullingham, R.E., Nicholls, A.J. & Kamm, B.R. Clinical pharmacokinetics of mycophenolate mofetil. Clin. Pharmacokinet. 34, 429-455 (1998).
2. Kuypers, D.R. et al. Twelve-month evaluation of the clinical pharmacokinetics of total and free mycophenolic acid and its glucuronide metabolites in renal allograft recipients on low dose tacrolimus in combination with mycophenolate mofetil. Ther. Drug Monit. 25, 609-622 (2003).
3. Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. European Mycophenolate Mofetil Cooperative Study Group. Lancet 345, 1321-1325 (1995).
4. Hardinger, K.L., Brennan, D.C., Lowell, J. & Schnitzler, M.A. Long-term outcome of gastrointestinal complications in renal transplant patients treated with mycophenolate mofetil. Transpl. Int. 17, 609-616 (2004).
5. Knoll, G.A., MacDonald, I., Khan, A. & Van Walraven, C. Mycophenolate mofetil dose reduction and the risk of acute rejection after renal transplantation. J. Am. Soc. Nephrol. 14, 2381-2386 (2003).
6. Roberti, I. & Reisman, L. A comparative analysis of the use of mycophenolate mofetil in pediatric vs. adult renal allograft recipients. Pediatr. Transplant. 3, 231-235 (1999).
7. Goebel, J., Logan, B., Maseck, D., DeRotte, M., Tarabishi, R. & Vinks, A. Pharmacokinetic, -dynamic and clinical variability of mycophenolate mofetil in pediatric kidney transplantation. Pediatr. Transplant. 11 (suppl. 1), 59 (2007).
8. Shaw, L.M., Korecka, M., Venkataramanan, R., Goldberg, L., Bloom, R. & Brayman, K.L. Mycophenolic acid pharmacodynamics and pharmacokinetics provide a basis for rational monitoring strategies. Am. J. Transplant. 3, 534-542 (2003).
9. Kuypers, D.R., Naesens, M., Vermeire, S. & Vanrenterghem, Y. 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 (2005).
10. van Gelder, T. et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther. Drug Monit. 28, 145-154 (2006).
11. Ettenger, R. & Sarwal, M.M. Mycophenolate mofetil in pediatric renal transplantation. Transplantation 80 (2 suppl.),S201-S210 (2005).
12. Hesselink, D.A. & van Gelder, T. Genetic and nongenetic determinants of between-patient variability in the pharmacokinetics of mycophenolic acid. Clin. Pharmacol. Ther. 78, 317-321 (2005).
13. Shaw, L.M., Nawrocki, A., Korecka, M., Solari, S. & Kang, J. Using established immunosuppressant therapy efectively: lessons from the measurement of mycophenolic acid plasma concentrations. Ther. Drug Monit. 26, 347-351 (2004).
14. Strassburg, C.P., Oldhafer, K., Manns, M.P. & Tukey, R.H. Diferential expression of the UGT1A locus in human liver, biliary, and gastric tissue: identifcation of UGT1A7 and UGT1A10 transcripts in extrahepatic tissue. Mol. Pharmacol. 52, 212-220 (1997).
15. Djebli, N., Picard, N., Rérolle, J.P., Le Meur, Y. & Marquet, P. Infuence 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 (2007).
16. Strassburg, C.P., Strassburg, A., Nguyen, N., Li, Q., Manns, M.P. & Tukey, R.H. Regulation and function of family 1 and family 2 UDP-glucuronosyltransferase genes (UGT1A, UGT2B) in human oesophagus. Biochem. J. 338, 489-498 (1999).
17. Bernard, O. & Guillemette, C. The main role of UGT1A9 in the hepatic metabolism of mycophenolic acid and the efects of naturally occurring variants. Drug Metab. Dispos. 32, 775-778 (2004).
18. Girard, H. et al. Identifcation 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 (2004).
19. Baldelli, S. et al. C-440T/T-331C polymorphisms in the UGT1A9 gene afect the pharmacokinetics of mycophenolic acid in kidney transplantation. Pharmacogenomics 8, 1127-1141 (2007).
20. Tukey, R.H. & Strassburg, C.P. Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu. Rev. Pharmacol. Toxicol. 40, 581-616 (2000).
21. Huang, Y.H. et al. Identifcation and functional characterization of UDP-glucuronosyltransferases UGT1A8*1, UGT1A8*2 and UGT1A8*3. Pharmacogenetics 12, 287-297 (2002).
22. Bernard, O., Tojcic, J., Journault, K., Perusse, L. & Guillemette, C. Infuence 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 (2006).
23. van Agteren, M. et al. AcylMPAG plasma concentrations and mycophenolic acid-related side efects in patients undergoing renal transplantation are not related to the UGT2B7-840G>A gene polymorphism. Ther. Drug Monit. 30, 439-444 (2008).
24. Heller, T. et al. Plasma concentrations of mycophenolic acid acyl glucuronide are not associated with diarrhea in renal transplant recipients. Am. J. Transplant. 7, 1822-1831 (2007).
25. Levesque, E. et al. The impact of UGT1A8, UGT1A9, and UGT2B7 genetic polymorphisms on the pharmacokinetic profle of mycophenolic acid after a single oral dose in healthy volunteers. Clin. Pharmacol. Ther. 81, 392-400 (2007).
26. Nebert, D.W. Extreme discordant phenotype methodology: an intuitive approach to clinical pharmacogenetics. Eur. J. Pharmacol. 410, 107-120 (2000).