A Gilbert's syndrome UGT1A1 variant confers susceptibility to tranilast-induced hyperbilirubinemia.
Tranilast (N-(3'4'-demethoxycinnamoyl)-anthranilic acid (N-5)) is an investigational drug for the prevention of restenosis following percutaneous transluminal coronary revascularization. An increase in bilirubin levels was observed in 12% of patients upon administration of tranilast in a phase III clinical trial. To identify the potential genetic factors that may account for the drug-induced hyperbilirubinemia, we examined polymorphisms in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene in over a thousand patients. Our results suggested that the TA repeat polymorphism in UGT1A1, which predisposes some individuals to Gilbert's syndrome, predicted the susceptibility to tranilast-induced hyperbilirubinemia. The (TA)(7)/(TA)(7) genotype was present in 39% of the 127 hyperbilirubinemic patients vs 7% of the 909 controls (P=2 x 10(-22)). Rapid identification of genetic factors accounting for the observed adverse effect during the course of a double-blind clinical trial demonstrated the potential application of pharmacogenetics in the clinical development of safe and effective medicines.
Danoff
T M
TM
Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, Philadelphia, PA, USA.
Campbell
D A
DA
McCarthy
L C
LC
Lewis
K F
KF
Repasch
M H
MH
Saunders
A M
AM
Spurr
N K
NK
Purvis
I J
IJ
Roses
A D
AD
Xu
C-F
CF
D018900:Dinucleotide Repeats / Q000235:genetics; D004311:Double-Blind Method; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005878:Gilbert Disease / Q000201:enzymology* / Q000235:genetics*; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced / Q000235:genetics*; D007527:Isoenzymes / Q000235:genetics; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D062367:ortho-Aminobenzoates / Q000009:adverse effects*; D000099148:UGT1A1 Enzyme
D014453:Glucuronosyltransferase; D007527:Isoenzymes; D062367:ortho-Aminobenzoates; D000099148:UGT1A1 Enzyme; C012293:tranilast