UGT genotype may contribute to adverse events following medication with mycophenolate mofetil in pediatric kidney transplant recipients.
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 after MMF dose reduction or discontinuation were compared with those of 22 children who tolerated the drug at standard doses. DNA was extracted and sequenced using standard procedures to detect polymorphisms associated with increased (e.g., UGT1A9 -331T>C) or decreased drug exposure. All three patients who were homozygous for UGT1A9 -331T>C developed leukopenia, and heterozygotes also had significantly more toxicity (P = 0.04). A weaker association (P = 0.08) existed in UGT2B7 -900G>A carriers. Our data implicate UGT polymorphisms associated with altered drug exposure as potential predictors of MMF adverse events.
Prausa
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SE
Division of Pharmacy, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Fukuda
T
T
Maseck
D
D
Curtsinger
K L
KL
Liu
C
C
Zhang
K
K
Nick
T G
TG
Sherbotie
J R
JR
Ellis
E N
EN
Goebel
J
J
Vinks
A A
AA
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D016030:Kidney Transplantation; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D010865:Pilot Projects; D011110:Polymorphism, Genetic
D007166:Immunosuppressive Agents; D014453:Glucuronosyltransferase; D009173:Mycophenolic Acid