Severe toxicities after irinotecan-based chemotherapy in a patient with lung cancer: a homozygote for the SLCO1B1*15 allele.
Irinotecan is used widely in the treatment of several malignancies, but unpredictable severe toxicities such as myelosuppression and delayed-type diarrhea are sometimes experienced. Polymorphism of the UGT1A1 gene is one of the likely reasons for interindividual differences in irinotecan pharmacokinetics and severe toxicity. Also, polymorphic organic anion-transporting polypeptide 1B1 (OATP1B1, SLCO1B1) is reported to be involved in the hepatocellular uptake of SN-38. A 61-year-old man with lung cancer developed severe toxicities, including grade 3 diarrhea, grade 4 leukopenia, and grade 4 neutropenia, after the first cycle of irinotecan (60 mg/m) plus cisplatin chemotherapy. The irinotecan and SN-38 areas under the concentration-time curve from time zero to infinity in this patient were 43% and 87% higher than the corresponding mean values for 10 other patients with lung cancer treated with irinotecan (60-100 mg/m) normalized for the dose of irinotecan. Analysis of genetic variants in genes encoding the drug-metabolizing enzyme (UGT1A1) and transporter (SLCO1B1) involving irinotecan disposition revealed that this patient was homozygous for the SLCO1B1*15 allele, which may result in severe toxicities attributable to the extensive accumulation of SN-38. Screening of SLCO1B1*15 is suggested to be useful in irinotecan chemotherapy to avoid unpredicted severe toxicity, although the homozygous genotype is rare among the Japanese.
Takane
Hiroshi
H
Department of Pharmacy, Tottori University Hospital, Yonago, Japan.
Miyata
Masanori
M
Burioka
Naoto
N
Kurai
Jun
J
Fukuoka
Yasushi
Y
Suyama
Hisashi
H
Shigeoka
Yasushi
Y
Otsubo
Kenji
K
Ieiri
Ichiro
I
Shimizu
Eiji
E
D000483:Alleles; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D044466:Asian People / Q000235:genetics; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives*; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000175:diagnosis* / Q000209:etiology / Q000235:genetics; D003937:Diagnosis, Differential; D006801:Humans; D000077146:Irinotecan; D007564:Japan; D027381:Liver-Specific Organic Anion Transporter 1; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics*; D011110:Polymorphism, Genetic
D000972:Antineoplastic Agents, Phytogenic; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D000077146:Irinotecan; D002166:Camptothecin