title: Exploring the intracellular pharmacokinetics of the 5-fluorouracil nucleotides during capecitabine treatment.
abstract: OBJECTIVE
  Three intracellularly formed metabolites are responsible for the antineoplastic effect of capecitabine: 5-fluorouridine 5'-triphosphate (FUTP), 5-fluoro-2'-deoxyuridine 5'-triphosphate (FdUTP), and 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP). The objective of this study was to explore the pharmacokinetics of these intracellular metabolites during capecitabine treatment.
  
  
  METHODS
  Serial plasma and peripheral blood mononuclear cell (PBMC) samples were collected from 13 patients treated with capecitabine 1000 mg QD (group A) and eight patients receiving capecitabine 850 mg m(-2) BID for fourteen days, every three weeks (group B). Samples were collected on day 1 and, for four patients of group B, also on day 14. The capecitabine and 5-fluorouracil (5-FU) plasma concentrations and intracellular metabolite concentrations were determined using LC-MS/MS. Pharmacokinetic parameters were estimated using non-compartmental analysis.
  
  
  RESULTS
  Only FUTP could be measured in the PBMC samples. The FdUTP and FdUMP concentrations were below the detection limits (LOD). No significant correlation was found between the plasma 5-FU and intracellular FUTP exposure. The FUTP concentration-time profiles demonstrated considerable inter-individual variation and accumulation of the metabolite in PBMCs. FUTP levels ranged between <LOD and 1.0 μM on day 1, and from 0.64 to 14 μM on day 14. The area under the FUTP concentration-time curve was significantly increased on day 14 of the treatment compared to day 1 (mean ± SD: 28 ± 19 μM h vs. 2.0 ± 1.9 μM h).
  
  
  CONCLUSIONS
  To our knowledge, this is the first time that intracellular FUTP concentrations were measured in patients treated with capecitabine. During 14 days of treatment with capecitabine twice daily, intracellular accumulation of FUTP occurs.
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek Hospital - The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.
authors.forename: Ellen J B
authors.initials: EJ
authors.lastname: Derissen
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek Hospital - The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.
authors.forename: Bart A W
authors.initials: BA
authors.lastname: Jacobs
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek Hospital - The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek Hospital - The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.
authors.forename: Hilde
authors.initials: H
authors.lastname: Rosing
authors.affiliation: Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.|Science Faculty, Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmaco-Epidemiology & Clinical Pharmacology, Utrecht University, P.O. Box 80082, 3508 TB, Utrecht, The Netherlands.
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek Hospital - The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.|Science Faculty, Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmaco-Epidemiology & Clinical Pharmacology, Utrecht University, P.O. Box 80082, 3508 TB, Utrecht, The Netherlands.
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D019540:Area Under Curve; D000069287:Capecitabine / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D002853:Chromatography, Liquid; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D003856:Deoxyuracil Nucleotides / Q000032:analysis / Q000493:pharmacokinetics*; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000032:analysis / Q000493:pharmacokinetics; D005472:Fluorouracil / Q000097:blood; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy*; D053719:Tandem Mass Spectrometry; D014544:Uridine Triphosphate / Q000031:analogs & derivatives* / Q000032:analysis / Q000493:pharmacokinetics
chemical_list: C576827:5-fluoro-2'-deoxyuridine; C105691:5-formyl-2'-deoxyuridine 5'-triphosphate; D000964:Antimetabolites, Antineoplastic; D003856:Deoxyuracil Nucleotides; C025635:5-fluorouridine 5'-triphosphate; D000069287:Capecitabine; D005472:Fluorouracil; D014544:Uridine Triphosphate; D003857:Deoxyuridine
keywords: 5-fluorouracil; 5-fluorouridine triphosphate (FUTP); capecitabine; nucleotides; peripheral blood mononuclear cells (PBMCs); pharmacokinetics