UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity.
The metabolism of irinotecan (CPT-11) involves sequential activation to SN-38 and detoxification to the pharmacologically inactive SN-38 glucuronide (SN-38G). We have previously demonstrated the role of UGT1A1 enzyme in the glucuronidation of SN-38 and a significant correlation between in vitro glucuronidation of SN-38 and UGT1A1 gene promoter polymorphism. This polymorphism (UGT1A1*28) is characterized by the presence of an additional TA repeat in the TATA sequence of the UGT1A1 promoter, ((TA)7TAA, instead of (TA)6TAA). Here we report the results from a prospective clinical pharmacogenetic study to determine the significance of UGT1A1*28 polymorphism on irinotecan disposition and toxicity in patients with cancer. Twenty patients with solid tumors were treated with a 90 min i.v. infusion of irinotecan (300 mg m(-2)) once every 3 weeks. The frequency of UGT1A1 genotypes was as follows: 6/6--45%, 6/7--35% and 7/7--20%, with allele frequencies of 0.375 and 0.625 for (TA)7TAA and (TA)6TAA, respectively. Patients with the (TA)7TAA polymorphism had significantly lower SN-38 glucuronidation rates than those with the normal allele (6/6>6/7>7/7, P = 0.001). More severe grades of diarrhea and neutropenia were observed only in patients heterozygous (grade 4 diarrhea, n = 1) or homozygous (grade 3 diarrhea/grade 4 neutropenia, n = 1 and grade 3 neutropenia, n = 1) for the (TA)7TAA sequence. The results suggest that screening for UGT1A1*28 polymorphism may identify patients with lower SN-38 glucuronidation rates and greater susceptibility to irinotecan induced gastrointestinal and bone marrow toxicity.
Iyer
L
L
Department of Medicine, The University of Chicago, IL, USA.
Das
S
S
Janisch
L
L
Wen
M
M
Ramírez
J
J
Karrison
T
T
Fleming
G F
GF
Vokes
E E
EE
Schilsky
R L
RL
Ratain
M J
MJ
D000328:Adult; D000483:Alleles; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D005838:Genotype; D020719:Glucuronides / Q000493:pharmacokinetics; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D008297:Male; D011110:Polymorphism, Genetic
C441475:7-ethyl-10-hydroxycamptothecin glucuronide; D000972:Antineoplastic Agents, Phytogenic; D020719:Glucuronides; D000077146:Irinotecan; D014453:Glucuronosyltransferase; D002166:Camptothecin