Abstract
Introduction
To explore severe toxicities induced by irinotecan-based chemotherapy and UGT1A1*6/*28 and SLCO1B1*15/*15 genotypes.
Case report
A 66-year-old Japanese male diagnosed with left pharyngeal carcinoma (T2N2bM0, stage IVA) was treated with irinotecan (70 mg/m2) on days 1, 8 and 15 in combination with docetaxel (60 mg/m2) on day 1 of a 28-day cycle. After the first cycle, he suffered marked toxicities, including grade 4 diarrhea and febrile grade 4 neutropenia. Plasma concentrations of irinotecan, SN-38 and SN-38G were measured, and extensive accumulation of SN-38 was observed. Genotyping of UGT1A1 and OATP1B1 proteins showed UGT1A1*6/*28 and SLCO1B1*15/*15, respectively, which are known to lead to extremely low glucuronidation and transport activities of substrate drugs.
Conclusion
The severe toxicities in this patient are attributable to the extensive accumulation of SN-38, which may result from a synergistic or additive effect of low metabolic (UGT1A1*6/*28) and transport (SLCO1B1*15/*15) capabilities.
Similar content being viewed by others
References
Kawato Y, Aonuma M, Hirota Y, Kuga H, Sato K (1991) Intracellular roles of SN-38, a metabolite of camptothecin derivative CPT-11, in the antitumor effect of CPT-11. Cancer Res 51:4187–4191
Iyer L, King CD, Whitington PF, Green MD, Roy SK, Tephly TR, Coffman BL, Ratain MJ (1998) Genetic predisposition to the metabolism of irinotecan (CPT-11): role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest 101:847–854
Mathijssen RH, van Alphen RJ, Verweij J, Loos WJ, Nooter K, Stoter G, Sparreboom A (2001) Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res 7:2182–2194
Chabot GG, Abigerges D, Catimel G, Culine S, de Forni M, Extra JM, Mahjoubi M, Herait P, Armand JP, Bugat R, Clavel M, Marty ME (1995) Population pharmacokinetics and pharmacodynamics of irinotecan (CPT-11) and active metabolite SN-38 during phase I trials. Ann Oncol 6:141–151
Kudoh S, Fukuoka M, Masuda N, Yoshikawa A, Kusunoki Y, Matsui K, Negoro S, Takifuji N, Nakagawa K, Hirashima T, Yana T, Takada M (1995) Relationship between the pharmacokinetics of irinotecan and diarrhea during combination chemotherapy with cisplatin. Jpn J Cancer Res 86:406–413
Ando Y, Saka H, Ando M, Sawa T, Muro K, Ueoka H, Yokoyama A, Saitoh S, Shimokata K, Hasegawa Y (2000) Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res 60:6921–6926
Toffoli G, Cecchin E, Corona G, Russo A, Buonadonna A, D’Andrea M, Pasetto LM, Pessa S, Errante D, De Pangher V, Giusto M, Medici M, Gaion F, Sandri P, Galligioni E, Bonura S, Boccalon M, Biason P, Frustaci S (2006) The role of UGT1A1*28 polymorphism in the pharmacodynamics and pharmacokinetics of irinotecan in patients with metastatic colorectal cancer. J Clin Oncol 24:3061–3068
Jada SR, Lim R, Wong CI, Shu X, Lee SC, Zhou Q, Goh BC, Chowbay B (2007) Role of UGT1A1*6, UGT1A1*28 and ABCG2 c.421C>A polymorphisms in irinotecan-induced neutropenia in Asian cancer patients. Cancer Sci 98:1461–1467
Minami H, Sai K, Saeki M, Saito Y, Ozawa S, Suzuki K, Kaniwa N, Sawada J, Hamaguchi T, Yamamoto N, Shirao K, Yamada Y, Ohmatsu H, Kubota K, Yoshida T, Ohtsu A, Saijo N (2007) Irinotecan pharmacokinetics/pharmacodynamics and UGT1A genetic polymorphisms in Japanese: roles of UGT1A1*6 and *28. Pharmacogenet Genomics 17:497–504
Han JY, Lim HS, Shin ES, Yoo YK, Park YH, Lee JE, Jang IJ, Lee DH, Lee JS (2006) Comprehensive analysis of UGT1A polymorphisms predictive for pharmacokinetics and treatment outcome in patients with non-small-cell lung cancer treated with irinotecan and cisplatin. J Clin Oncol 24:2237–2244
Nozawa T, Minami H, Sugiura S, Tsuji A, Tamai I (2005) Role of organic anion transporter OATP1B1 (OATP-C) in hepatic uptake of irinotecan and its active metabolite, 7-ethyl-10-hydroxycamptothecin: in vitro evidence and effect of single nucleotide polymorphisms. Drug Metab Dispos 33:434–439
Xiang X, Jada SR, Li HH, Fan L, Tham LS, Wong CI, Lee SC, Lim R, Zhou QY, Goh BC, Tan EH, Chowbay B (2006) Pharmacogenetics of SLCO1B1 gene and the impact of *1b and *15 haplotypes on irinotecan disposition in Asian cancer patients. Pharmacogenet Genomics 16:683–691
Takane H, Miyata M, Burioka N, Kurai J, Fukuoka Y, Suyama H, Shigeoka Y, Otsubo K, Ieiri I, Shimizu E (2007) Severe toxicities after irinotecan-based chemotherapy in a patient with lung cancer: a homozygote for the SLCO1B1*15 allele. Ther Drug Monit 29:666–668
Han JY, Lim HS, Shin ES, Yoo YK, Park YH, Lee JE, Kim HT, Lee JS (2008) Influence of the organic anion-transporting polypeptide 1B1 (OATP1B1) polymorphisms on irinotecan-pharmacokinetics and clinical outcome of patients with advanced non-small cell lung cancer. Lung Cancer 59:69–75
Rivory LP, Robert J (1995) Identification and kinetics of a β-glucuronide metabolite of SN-38 in human plasma after administration of the camptothecin derivative irinotecan. Cancer Chemother Pharmacol 36:176–179
Sparreboom A, de Bruijn P, de Jonge MJ, Loos WJ, Stoter G, Verweij J, Nooter K (1998) Liquid chromatographic determined of irinotecan and three major metabolites in human plasma, urine and feces. J Chromatogr B Biomed Sci Appl 721:225–235
Klein CE, Gupta E, Reid JM, Atherton PJ, Sloan JA, Pitot HC, Ratain MJ, Kastrissios H (2002) Population pharmacokinetic model for irinotecan and two of its metabolites, SN-38 and SN-38 glucuronide. Clin Pharmacol Ther 72:638–647
Marre F, Sanderink GJ, de Sousa G, Gaillard C, Martinet M, Rahmani R (1996) Hepatic biotransformation of docetaxel (Taxotere) in vitro: involvement of the CYP3A subfamily in humans. Cancer Res 56:1296–1302
Smith NF, Figg WD, Sparreboom A (2006) Pharmacogenetics of irinotecan metabolism and transport: an update. Toxicol In Vitro 20:163–175
Han JY, Lim HS, Park YH, Lee SY, Lee JS (2008) Integrated pharmacogenetic prediction of irinotecan pharmacokinetics and toxicity in patients with advanced non-small cell lung cancer. Lung Cancer. doi:10.1016/j.lungcan.2007.12.003
Nishizato NY, Ieiri I, Suzuki H, Kimura M, Kawabata K, Hirota T, Takane H, Irie S, Kusuhara H, Urasaki Y, Urae A, Higuchi S, Otsubo K, Sugiyama Y (2003) Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin Pharmacol Ther 73:554–565
Acknowledgments
This study is supported by Health and Labor Sciences Research Grants from the Ministry of Health, Labor and Welfare, Tokyo, Japan.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Takane, H., Kawamoto, K., Sasaki, T. et al. Life-threatening toxicities in a patient with UGT1A1*6/*28 and SLCO1B1*15/*15 genotypes after irinotecan-based chemotherapy. Cancer Chemother Pharmacol 63, 1165–1169 (2009). https://doi.org/10.1007/s00280-008-0864-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-008-0864-x