title: Does saturable formation of gemcitabine triphosphate occur in patients?
abstract: OBJECTIVE
  This study aims to determine if intracellular formation of gemcitabine triphosphate (dFdCTP), an active metabolite of gemcitabine, is saturable at doses used for treatment of Asian patients with lung cancer.
  
  
  METHODS
  From a phase II trial, plasma concentrations of gemcitabine, its inactive metabolite 2'-2'-difluorodeoxyuridine (dFdU), and mononuclear cell concentrations of gemcitabine-triphosphate were measured in 56 and 33 patients, respectively. The pharmacokinetics of gemcitabine and metabolites were modeled using nonlinear mixed effects modeling (NONMEM). A reduced dataset of ten randomly selected patients was employed to compare first-order and saturable formation of dFdCTP from gemcitabine.
  
  
  RESULTS
  The median population clearance estimate for dFdCTP formation with the full dataset was 70.2 L/h/70 kg/1.7 m. Modeling Michaelis-Menten formation of dFdCTP on a reduced dataset estimated K(m) to be 3.6 times higher than the maximum gemcitabine concentration (72.2 microM) measured in this study.
  
  
  CONCLUSIONS
  The results showed that first-order and nonsaturable clearance described intracellular dFdCTP formation at clinically applied doses of gemcitabine.
authors.affiliation: Department of Hematology-Oncology, National University Hospital, Singapore. tham_lai_san@lilly.com
authors.forename: Lai-San
authors.initials: LS
authors.lastname: Tham
authors.forename: Ling-Zhi
authors.initials: LZ
authors.lastname: Wang
authors.forename: Ross A
authors.initials: RA
authors.lastname: Soo
authors.forename: How-Sung
authors.initials: HS
authors.lastname: Lee
authors.forename: Soo-Chin
authors.initials: SC
authors.lastname: Lee
authors.forename: Boon-Cher
authors.initials: BC
authors.lastname: Goh
authors.forename: Nicholas H G
authors.initials: NH
authors.lastname: Holford
mesh_terms: D000273:Adipose Tissue; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001711:Biotransformation; D001835:Body Weight; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism*; D017322:Clinical Trials, Phase II as Topic; D003404:Creatinine / Q000097:blood; D003570:Cytidine Triphosphate / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011355:Prodrugs / Q000493:pharmacokinetics*; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D003841:Deoxycytidine; D003570:Cytidine Triphosphate; C533693:gemcitabine triphosphate; D003404:Creatinine; D016190:Carboplatin; D000093542:Gemcitabine