UGT Genotype May Contribute to Adverse Events Following Medication With Mycophenolate Mofetil in Pediatric Kidney Transplant Recipients

  title={UGT Genotype May Contribute to Adverse Events Following Medication With Mycophenolate Mofetil in Pediatric Kidney Transplant Recipients},
  author={Susie Prausa and Tsuyoshi Fukuda and Denise Maseck and Kristi L Curtsinger and C Liu and Kun Zhang and Todd G. Nick and Joseph R. Sherbotie and Eileen N. Ellis and Jens Goebel and Aatmm Vinks},
  journal={Clinical Pharmacology \& Therapeutics},
Leukopenia and diarrhea are the predominant adverse events associated with mycophenolate mofetil (MMF), leading to dose reduction or discontinuation in children. Polymorphisms of the drug's main metabolizing enzyme, uridine diphosphate–glucuronosyl transferase (UGT), confer alteration in drug exposure. We studied the incidence of these polymorphisms in pediatric kidney transplant recipients experiencing MMF‐associated leukopenia and diarrhea. UGT genotypes of 16 affected children who recovered… 
Mycophenolic acid-related diarrhea is not associated with polymorphisms in SLCO1B nor with ABCB1 in renal transplant recipients
Genotyping for ABCB1 or SLCO1B pretransplantation is unlikely to be of clinical value for individualization of MPA therapy.
UGT1A9, UGT2B7, and MRP2 Genotypes Can Predict Mycophenolic Acid Pharmacokinetic Variability in Pediatric Kidney Transplant Recipients
It is demonstrated that combined UGT1A9-440C>T, UGT2B7-900A>G, and MRP2-24T>C polymorphisms can be important predictors of interindividual variability in MPA exposure in the pediatric population.
Mycophenolate mofetil‐related leukopenia in children and young adults following kidney transplantation: Influence of genes and drugs
Time to leukopenia did not differ between patients by induction agent, but 2 SNPs in IMPDH1 were associated with increased time to leucopenia and UGT2B7 may influence leuk Openia risk especially in patients without lymphocyte‐depleting induction.
Influence of Polymorphisms on Mycophenolate Mofetil - Induced Diarrhoea in Renal Transplanted Children
IMPDH2  (IVS7+10T>C) and ABCC2 -24CC wild-type patients carrying IMPDH1 IVS7 + 10 T>C variant are biomarkers associated with diarrhoea in children treated with MMF.
Population Pharmacokinetics and Pharmacogenetics of Mycophenolic Acid Following Administration of Mycophenolate Mofetil in De Novo Pediatric Renal‐Transplant Patients
Body weight, concomitant medication, and UGT2B7 genotype contribute significantly to the interindividual variability of MMF disposition in pediatric renal‐transplant patients.
The influence of UGT polymorphisms as biomarkers in solid organ transplantation.
Age-Related Variability of Mycophenolate Mofetil Exposure in Stable Pediatric Liver Transplant Recipients and Influences of Donor Characteristics
A marked MPA underexposure was observed among young children receiving livers from pediatric donors, indicating that higher doses might be required to reach the same MPA exposure as in adolescents.
SLCO1B1 genetic polymorphism influences mycophenolic acid tolerance in renal transplant recipients.
Results suggest for the first time that carriers of the SLCO1B1*5 allele seem to be protected from MPA-related ADRs.
Effect of UGT polymorphisms on pharmacokinetics and adverse reactions of mycophenolic acid in kidney transplant patients.
The relevant literature is reviewed and significant influences of UGT polymorphisms, such as UGT1A8 (rs1042597, rs17863762) and UGT2B7 (rs7438135, rs7439366, rs7662029), on the pharmacokinetics of MPA and its metabolites and adverse reactions are summarized.


AcylMPAG Plasma Concentrations and Mycophenolic Acid-Related Side Effects in Patients Undergoing Renal Transplantation Are Not Related to the UGT2B7-840G>A Gene Polymorphism
No influence of the −840G>A UGT2B7 SNP on AcylMPAG exposure in patients undergoing renal transplantation is found and there also was no association between this variant genotype and the incidence of diarrhea or leucopenia, two adverse events for which a role for Ayl-glucuronide metabolite has been suggested.
C-440T/T-331C polymorphisms in the UGT1A9 gene affect the pharmacokinetics of mycophenolic acid in kidney transplantation.
The study demonstrated a significant impact of C-440T/T-331C SNPs in the promoter region of the UGT1A9 gene on MPA pharmacokinetics in renal allograft recipients and confirmed large interpatient variability of MPA exposure.
Influence of the UGT2B7 promoter region and exon 2 polymorphisms and comedications on Acyl-MPAG production in vitro and in adult renal transplant patients
In vitro and in vivo, AcMPAG production was increased in corticosteroid-induced rat liver microsomes, consistent with the observed in-vivo decrease of mycophenolic acid metabolites AUC0–9 h/dose with time after transplant.
Influence of Nonsynonymous Polymorphisms of UGT1A8 and UGT2B7 Metabolizing Enzymes on the Formation of Phenolic and Acyl Glucuronides of Mycophenolic Acid
Several UGT1A8 variants identified may potentially account for the large interindividual variance in MMF pharmacokinetics and deserve further clinical investigations.
Plasma Concentrations of Mycophenolic Acid Acyl Glucuronide Are Not Associated with Diarrhea in Renal Transplant Recipients
  • T. Heller, T. van Gelder, V. Armstrong
  • Medicine, Biology
    American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
  • 2007
Data support the concept that CsA inhibits the biliary excretion of MPAG and AcMPAG, thereby potentially reducing the risk of intestinal injury through enterohepatic recycling of M PA and its metabolites.
A comparative analysis of the use of mycophenolate mofetil in pediatric vs. adult renal allograft recipients
The possibility that the optimum dose, dosing interval or preparation of MMF has not yet been established for pediatric patients is suggested, and one should monitor pediatric patients closely, especially the small ones, to avoid significant nutritional problems and other adverse GI events.
The main role of UGT1A9 in the hepatic metabolism of mycophenolic acid and the effects of naturally occurring variants.
Preliminary evidences that genetic factors, especially in the hepatic UGT1A9, may contribute to the variability of MPA pharmacokinetics observed in transplant patients are provided.
The Impact of UGT1A8, UGT1A9, and UGT2B7 Genetic Polymorphisms on the Pharmacokinetic Profile of Mycophenolic Acid After a Single Oral Dose in Healthy Volunteers
After a single oral dose of MMF in healthy volunteers, specific UGT genotypes significantly alter MPA PKs and this clearly warrants additional studies with complete and detailed genetic profiling of UGT 1A8, UGT1A9, and UGT2B7 genes.
Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. European Mycophenolate Mofetil Cooperative Study Group.
  • Medicine
  • 1995
MMF significantly reduced the rate of biopsy-proven rejection or other treatment failure during the first 6 months after transplantation and was well tolerated, although the 3 g dose was somewhat less well tolerated.