title: Human mass balance study of TAS-102 using (14)C analyzed by accelerator mass spectrometry.
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 [(14)C]-FTD, while patients in group B (N = 4) received 60 mg TAS-102 with 1000 nCi [(14)C]-TPI orally. Plasma, blood, urine, feces, and expired air (group A only) were collected up to 168 h and were analyzed for (14)C by accelerator mass spectrometry and analytes by LC-MS/MS.
  
  
  RESULTS
  FTD: 59.8% of the (14)C 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 (14)C 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.
  
  
  CONCLUSIONS
  Absorbed (14)C-FTD was metabolized and mostly excreted in urine. The majority of (14)C-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.
authors.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Hillman Research Pavilion, Suite G27E, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA.|Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Taiho Oncology Inc., Princeton, NJ, USA.
authors.forename: Jabed
authors.initials: J
authors.lastname: Seraj
authors.affiliation: Taiho Oncology Inc., Princeton, NJ, USA.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Taiho Oncology Inc., Princeton, NJ, USA.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Mizuguchi
authors.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Hillman Research Pavilion, Suite G27E, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Strychor
authors.affiliation: Clinical Research Services, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Jillian
authors.initials: J
authors.lastname: Fiejdasz
authors.affiliation: Clinical Research Services, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Tyeler
authors.initials: T
authors.lastname: Faulkner
authors.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Hillman Research Pavilion, Suite G27E, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Parise
authors.affiliation: Clinical Research Services, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Fawcett
authors.affiliation: Clinical Research Services, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Pollice
authors.affiliation: Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Mason
authors.affiliation: Xceleron Inc., Germantown, MD, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hague
authors.affiliation: Xceleron Inc., Germantown, MD, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Croft
authors.affiliation: Xceleron Inc., Germantown, MD, USA.
authors.forename: James
authors.initials: J
authors.lastname: Nugteren
authors.affiliation: INC Research LLC, Raleigh, NC, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Tedder
authors.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Hillman Research Pavilion, Suite G27E, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA.|Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Weijing
authors.initials: W
authors.lastname: Sun
authors.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Hillman Research Pavilion, Suite G27E, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA.|Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Chu
authors.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Hillman Research Pavilion, Suite G27E, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA. beumerj@gmail.com.|Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. beumerj@gmail.com.|Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA. beumerj@gmail.com.
authors.forename: Jan Hendrik
authors.initials: JH
authors.lastname: Beumer
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002853:Chromatography, Liquid / Q000379:methods; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011743:Pyrimidines / Q000493:pharmacokinetics*; D011759:Pyrrolidines; D053719:Tandem Mass Spectrometry / Q000379:methods; D013939:Thymidine Phosphorylase / Q000378:metabolism; D013941:Thymine; D014271:Trifluridine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D011743:Pyrimidines; D011759:Pyrrolidines; C000613803:trifluridine tipiracil drug combination; C401928:trifluoromethyluracil; D014498:Uracil; D013939:Thymidine Phosphorylase; D013941:Thymine; D014271:Trifluridine
keywords: Excretion; Mass balance; Metabolism; Radiolabel; Trifluorothymidine