Risk of diarrhoea in a long-term cohort of renal transplant patients given mycophenolate mofetil: the significant role of the UGT1A8 2 variant allele.
OBJECTIVE
In renal transplant patients given mycophenolate mofetil (MMF), we investigated the relationship between the digestive adverse events and polymorphisms in the UGT genes involved in mycophenolic acid (MPA) intestinal metabolism and biliary excretion of its phase II metabolites.


METHODS
Clinical data and DNA from 256 patients transplanted between 1996 and 2006 and given MMF with cyclosporin (CsA, n = 185), tacrolimus (TAC, n = 49) or sirolimus (SIR, n = 22), were retrospectively analysed. The relationships between diarrhoea and polymorphisms in UGT1A8 (2; 518C>G, 3; 830G>A), UGT1A7 (622C>T), UGT1A9 (-275T>A), UGT2B7 (-840G>A) and ABCC2 (-24C>T, 3972C>T) or the co-administered immunosuppressant were investigated using the Cox proportional hazard model.


RESULTS
Multivariate analysis showed that patients on TAC or SIR had a 2.8 higher risk of diarrhoea than patients on CsA (HR = 2.809; 95%CI (1.730, 4.545); P < 0.0001) and that non-carriers of the UGT1A8 2 allele (CC518 genotype) had a higher risk of diarrhoea than carriers (C518G and 518GG genotypes) (HR = 1.876; 95%CI (1.109, 3.175); P = 0.0192). When patients were divided according to the immunosuppressive co-treatment, a significant effect of UGT1A8 2 was found in those co-treated with CsA (HR = 2.414; 95%CI (1.089, 5.354); P = 0.0301) but not TAC or SIR (P = 0.4331).


CONCLUSIONS
These results suggest that a possible inhibition of biliary excretion of MPA metabolites by CsA and a decreased intestinal production of these metabolites in UGT1A8 2 carriers may be protective factors against MMF-induced diarrhoea.
Woillard
Jean-Baptiste
JB
Inserm, UMR S-850, Limoges, France.
Rerolle
Jean-Philippe
JP
Picard
Nicolas
N
Rousseau
Annick
A
Drouet
Mireille
M
Munteanu
Eliza
E
Essig
Marie
M
Marquet
Pierre
P
Le Meur
Yann
Y
D000328:Adult; D015331:Cohort Studies; D016572:Cyclosporine / Q000008:administration & dosage; D003967:Diarrhea / Q000139:chemically induced* / Q000235:genetics*; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000401:mortality; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D015999:Multivariate Analysis; D009173:Mycophenolic Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide / Q000502:physiology*; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012306:Risk; D020123:Sirolimus / Q000008:administration & dosage; D016019:Survival Analysis; D016559:Tacrolimus / Q000008:administration & dosage
C000715087:ABCC2 protein, human; D004338:Drug Combinations; D007166:Immunosuppressive Agents; D000089762:Multidrug Resistance-Associated Protein 2; D016572:Cyclosporine; D014453:Glucuronosyltransferase; C454320:UDP-glucuronosyltransferase, UGT1A8; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus