Ayako Tsuboya1,2, Yutaro Kubota3, Hiroo Ishida3, Ryotaro Ohkuma3, Tomoyuki Ishiguro3, Yuya Hirasawa3, Hirotsugu Ariizumi3, Takuya Tsunoda3, Yasutsuna Sasaki3, Natsumi Matsumoto4, Yusuke Kondo5, Yukana Tomoda5, Hiroyuki Kusuhara5, Ken-Ichi Fujita6. 1. Division of Pharmaceutical Regulatory Pharmacy, Department of Healthcare and Regulatory Sciences, Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan. 2. Department of Pharmacy, Kawasaki Municipal Tama Hospital, 1‑30‑37, Shukugawara, Tama‑ku, Kawasaki, Kanagawa, 214‑8525, Japan. 3. Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan. 4. Division of Cancer Genome and Pharmacotherapy, Department of Clinical Pharmacy, Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan. 5. Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongou, Bunkyo-ku, Tokyo, 113-0033, Japan. 6. Division of Cancer Genome and Pharmacotherapy, Department of Clinical Pharmacy, Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan. k.fujita@med.showa-u.ac.jp.
Abstract
PURPOSE: SN-38, a pharmacologically active metabolite of irinotecan, is taken up into hepatocytes by organic anion transporting polypeptide (OATP) 1B1. The effects of functional OATP1B1 521T>C on the pharmacokinetics of SN-38 remain controversial. Here, we prospectively examined the effects of OATP1B1 function on the area under the plasma total or unbound concentration-time curve (tAUC or uAUC) of SN-38 by assessing OATP1B1 521T>C and the plasma levels of endogenous OATP1B1 substrates, coproporphyrin (CP)-I and III, in cancer patients treated with irinotecan. METHODS: We enrolled cancer patients who were treated with an irinotecan-containing regimen and did not have severe renal failure. The total and unbound concentrations of SN-38 in the plasma were measured by high-performance liquid chromatography. AUC values were calculated and normalized to the actual irinotecan dose (AUC/dose). The OATP1B1 521T>C was analyzed by direct sequencing. Concentrations of the endogenous substrates in plasma before irinotecan treatment (baseline) were determined by liquid chromatography with tandem mass spectrometry. RESULTS: Twenty-two patients with a median estimated glomerular filtration rate of 74.8 mL/min (range 32.6-99.6) were examined. Both tAUC/dose and uAUC/dose were associated with the grade of neutropenia; however, they were not associated with OATP1B1 521T>C or baseline CP-I and III levels. It is worth noting that these baseline concentrations were significantly higher in patients with OATP1B1 521C, supporting functional changes in OATP1B1. CONCLUSION: The contribution of OATP1B1 activity to inter-patient variability in the systemic exposure to SN-38 is likely minimal in patients without severe renal failure.
PURPOSE: SN-38, a pharmacologically active metabolite of irinotecan, is taken up into hepatocytes by organic anion transporting polypeptide (OATP) 1B1. The effects of functional OATP1B1 521T>C on the pharmacokinetics of SN-38 remain controversial. Here, we prospectively examined the effects of OATP1B1 function on the area under the plasma total or unbound concentration-time curve (tAUC or uAUC) of SN-38 by assessing OATP1B1 521T>C and the plasma levels of endogenous OATP1B1 substrates, coproporphyrin (CP)-I and III, in cancer patients treated with irinotecan. METHODS: We enrolled cancer patients who were treated with an irinotecan-containing regimen and did not have severe renal failure. The total and unbound concentrations of SN-38 in the plasma were measured by high-performance liquid chromatography. AUC values were calculated and normalized to the actual irinotecan dose (AUC/dose). The OATP1B1 521T>C was analyzed by direct sequencing. Concentrations of the endogenous substrates in plasma before irinotecan treatment (baseline) were determined by liquid chromatography with tandem mass spectrometry. RESULTS: Twenty-two patients with a median estimated glomerular filtration rate of 74.8 mL/min (range 32.6-99.6) were examined. Both tAUC/dose and uAUC/dose were associated with the grade of neutropenia; however, they were not associated with OATP1B1 521T>C or baseline CP-I and III levels. It is worth noting that these baseline concentrations were significantly higher in patients with OATP1B1 521C, supporting functional changes in OATP1B1. CONCLUSION: The contribution of OATP1B1 activity to inter-patient variability in the systemic exposure to SN-38 is likely minimal in patients without severe renal failure.
Authors: Y Ando; H Saka; M Ando; T Sawa; K Muro; H Ueoka; A Yokoyama; S Saitoh; K Shimokata; Y Hasegawa Journal: Cancer Res Date: 2000-12-15 Impact factor: 12.701
Authors: R H Mathijssen; R J van Alphen; J Verweij; W J Loos; K Nooter; G Stoter; A Sparreboom Journal: Clin Cancer Res Date: 2001-08 Impact factor: 12.531
Authors: Spinel Karas; Amy S Etheridge; Deborah A Nickerson; Nancy J Cox; Karen L Mohlke; Erika Cecchin; Giuseppe Toffoli; Ron H J Mathijssen; Alan Forrest; Robert R Bies; Federico Innocenti Journal: Br J Cancer Date: 2021-10-26 Impact factor: 9.075