Cancer Chemotherapy and Pharmacology

, Volume 77, Issue 3, pp 515–526

Human mass balance study of TAS-102 using 14C analyzed by accelerator mass spectrometry

  • James J. Lee
  • Jabed Seraj
  • Kenichiro Yoshida
  • Hirokazu Mizuguchi
  • Sandra Strychor
  • Jillian Fiejdasz
  • Tyeler Faulkner
  • Robert A. Parise
  • Patrick Fawcett
  • Laura Pollice
  • Scott Mason
  • Jeremy Hague
  • Marie Croft
  • James Nugteren
  • Charles Tedder
  • Weijing Sun
  • Edward Chu
  • Jan Hendrik Beumer
Original Article

DOI: 10.1007/s00280-016-2965-2

Cite this article as:
Lee, J.J., Seraj, J., Yoshida, K. et al. Cancer Chemother Pharmacol (2016) 77: 515. doi:10.1007/s00280-016-2965-2

Abstract

Background

TAS-102 is an oral fluoropyrimidine prodrug composed of trifluridine (FTD) and tipiracil hydrochloride (TPI) in a 1:0.5 ratio. FTD is a thymidine analog, and it is degraded by thymidine phosphorylase (TP) to the inactive trifluoromethyluracil (FTY) metabolite. TPI inhibits degradation of FTD by TP, increasing systemic exposure to FTD.

Methods

Patients with advanced solid tumors (6 M/2 F; median age 58 years; PS 0–1) were enrolled on this study. Patients in group A (N = 4) received 60 mg TAS-102 with 200 nCi [14C]-FTD, while patients in group B (N = 4) received 60 mg TAS-102 with 1000 nCi [14C]-TPI orally. Plasma, blood, urine, feces, and expired air (group A only) were collected up to 168 h and were analyzed for 14C by accelerator mass spectrometry and analytes by LC–MS/MS.

Results

FTD: 59.8 % of the 14C dose was recovered: 54.8 % in urine mostly as FTY and FTD glucuronide isomers. The extractable radioactivity in the pooled plasma consisted of 52.7 % FTD and 33.2 % FTY. TPI: 76.8 % of the 14C dose was recovered: 27.0 % in urine mostly as TPI and 49.7 % in feces. The extractable radioactivity in the pooled plasma consisted of 53.1 % TPI and 30.9 % 6-HMU, the major metabolite of TPI.

Conclusion

Absorbed 14C-FTD was metabolized and mostly excreted in urine. The majority of 14C-TPI was recovered in feces, and the majority of absorbed TPI was excreted in urine. The current data with the ongoing hepatic and renal dysfunction studies will provide an enhanced understanding of the TAS-102 elimination profile.

Keywords

Mass balance Trifluorothymidine Radiolabel Excretion Metabolism 

Funding information

Funder NameGrant NumberFunding Note
National Cancer Institute
  • P30CA047904
National Center for Research Resources
  • UL1 RR024153
Taiho

    Copyright information

    © Springer-Verlag Berlin Heidelberg 2016

    Authors and Affiliations

    • James J. Lee
      • 1
      • 2
    • Jabed Seraj
      • 3
    • Kenichiro Yoshida
      • 3
    • Hirokazu Mizuguchi
      • 3
    • Sandra Strychor
      • 1
    • Jillian Fiejdasz
      • 4
    • Tyeler Faulkner
      • 4
    • Robert A. Parise
      • 1
    • Patrick Fawcett
      • 4
    • Laura Pollice
      • 4
    • Scott Mason
      • 5
    • Jeremy Hague
      • 6
    • Marie Croft
      • 6
    • James Nugteren
      • 6
    • Charles Tedder
      • 7
    • Weijing Sun
      • 1
      • 2
    • Edward Chu
      • 1
      • 2
    • Jan Hendrik Beumer
      • 1
      • 2
      • 8
    1. 1.Cancer Therapeutics ProgramUniversity of Pittsburgh Cancer InstitutePittsburghUSA
    2. 2.Division of Hematology-Oncology, Department of MedicineUniversity of Pittsburgh School of MedicinePittsburghUSA
    3. 3.Taiho Oncology Inc.PrincetonUSA
    4. 4.Clinical Research ServicesUniversity of Pittsburgh Cancer InstitutePittsburghUSA
    5. 5.Department of RadiologyUniversity of PittsburghPittsburghUSA
    6. 6.Xceleron Inc.GermantownUSA
    7. 7.INC Research LLCRaleighUSA
    8. 8.Department of Pharmaceutical SciencesUniversity of Pittsburgh School of PharmacyPittsburghUSA

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