Severe toxicities after irinotecan-based chemotherapy in a patient with lung cancer: a homozygote for the SLCO1B1*15 allele.

Abstract

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.

• Authors: Hiroshi Takane, Masanori Miyata, Naoto Burioka, Jun Kurai, Yasushi Fukuoka, Hisashi Suyama, Yasushi Shigeoka, Kenji Otsubo, Ichiro Ieiri, Eiji Shimizu
• Journal: Therapeutic drug monitoring (Ther Drug Monit) Vol. 29 Issue 5 Pg. 666-8 (Oct 2007) ISSN: 0163-4356 [Print] United States
• PMID: 17898662 (Publication Type: Case Reports, Journal Article)

Chemical References

• Antineoplastic Agents, Phytogenic
• Liver-Specific Organic Anion Transporter 1
• Organic Anion Transporters
• SLCO1B1 protein, human
• Irinotecan
• Camptothecin

Topics

• Alleles
• Antineoplastic Agents, Phytogenic (adverse effects)
• Asian People (genetics)
• Camptothecin (adverse effects, analogs & derivatives)
• Chemical and Drug Induced Liver Injury (blood, diagnosis, etiology, genetics)
• Diagnosis, Differential
• Humans
• Irinotecan
• Japan
• Liver-Specific Organic Anion Transporter 1
• Lung Neoplasms (drug therapy)
• Male
• Middle Aged
• Organic Anion Transporters (genetics)
• Polymorphism, Genetic