Polymorphisms of UDP-glucuronosyltransferase and pharmacokinetics of irinotecan.
Irinotecan is a prodrug that is hydrolyzed by carboxylesterase in vivo to form an active metabolite SN-38. SN-38 is further conjugated and detoxified by UDP-glucuronosyltransferase (UGT) to yield its beta-glucuronide (SN-38G). Although irinotecan is widely used, the drug causes unpredictably severe, occasionally fatal, toxicity of leukopenia or diarrhea. Interindividual variation of sensitivity to irinotecan is related to large variations of biotransformation of the active metabolite SN-38, some of which would be caused by genetic polymorphism of UGT1A1, an isozyme responsible for the SN-38 glucuronidation. As a surrogate for the UGT activity, the polymorphic frequency distribution of the area under the concentration-time curve (AUC) ratios of SN-38 to SN-38G (AUC(SN-38)/AUC(SN-38G)) using pooled pharmacokinetic data from four independent study groups in Japan was explored. The data from 100 cancer patients was analyzed, including 14 who were genotyped for UGT1A1 gene in the previous studies. The median ratios of AUC(SN-38)/AUC(SN-38G) was 0.40 (interquartile range, 0.30 to 0.55; range, 0.09 to 2.32). Frequency distribution of the AUC (SN-38)/AUC(SN-38G) was skewed to the right without bimodality and the patient population could not be segregated into discrete subgroups that differ in the UGT activity by the AUC ratios. The 4 subjects carrying UGT1A1*28 allele had values of the AUC(SN-38)/AUC(SN-38G) above the 75th percentile of the total population, suggesting a potential pharmacogenetic/pharmacokinetic relationship. Ordinary values with a median of 0.41 (interquartile range, 0.33 to 0.49) were obtained for the UGT1A1*6 heterozygous patient and the 9 UGT1A1*1 homozygous patients (the reference sequence). The large variation in the UGT activity being related to the genetic status would warrant pharmacogenetic-guided dosing of irinotecan.
Ando
Yuichi
Y
First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya, Japan. yando@mail.nih.gov
Ueoka
Hiroshi
H
Sugiyama
Toru
T
Ichiki
Masao
M
Shimokata
Kaoru
K
Hasegawa
Yoshinori
Y
D000328:Adult; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001663:Bilirubin / Q000378:metabolism; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D004791:Enzyme Inhibitors / Q000097:blood; D005260:Female; D005965:Glucuronates / Q000097:blood; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics
C114685:7-ethyl-10-hydroxycamptothecin beta-glucuronide; D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D005965:Glucuronates; D000077146:Irinotecan; D014453:Glucuronosyltransferase; D001663:Bilirubin; D002166:Camptothecin