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/m(2)) on days 1, 8 and 15 in combination with docetaxel (60 mg/m(2)) 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.
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/m(2)) on days 1, 8 and 15 in combination with docetaxel (60 mg/m(2)) 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.
Authors: Evita van de Steeg; Els Wagenaar; Cornelia M M van der Kruijssen; Johanna E C Burggraaff; Dirk R de Waart; Ronald P J Oude Elferink; Kathryn E Kenworthy; Alfred H Schinkel Journal: J Clin Invest Date: 2010-07-19 Impact factor: 14.808
Authors: Evita van de Steeg; Viktor Stránecký; Hana Hartmannová; Lenka Nosková; Martin Hřebíček; Els Wagenaar; Anita van Esch; Dirk R de Waart; Ronald P J Oude Elferink; Kathryn E Kenworthy; Eva Sticová; Mohammad al-Edreesi; A S Knisely; Stanislav Kmoch; Milan Jirsa; Alfred H Schinkel Journal: J Clin Invest Date: 2012-01-09 Impact factor: 14.808
Authors: Wenjun Ni; Jia Ji; Zunyan Dai; Audrey Papp; Amy J Johnson; Sunjoo Ahn; Katherine L Farley; Thomas S Lin; James T Dalton; Xiaobai Li; David Jarjoura; John C Byrd; Wolfgang Sadee; Michael R Grever; Mitch A Phelps Journal: PLoS One Date: 2010-11-01 Impact factor: 3.240