title: Pharmacokinetics and pharmacogenetics of capecitabine and its metabolites following replicate administration of two 500 mg tablet formulations.
abstract: OBJECTIVE
  To describe concentration versus time profiles of capecitabine and its metabolites 5'-DFUR, 5'-DFCR and 5-FU, depending on tablet formulation and on frequent and/or relevant genetic polymorphisms of cytidine deaminase, dihydropyrimidine dehydrogenase, thymidylate synthase and methylenetetrahydrofolate reductase (MTHFR).
  
  
  METHODS
  In 46 cancer patients on chronic capecitabine treatment, who voluntarily participated in the study, individual therapeutic doses were replaced on four consecutive mornings by the study medication. The appropriate number of 500 mg test (T) or reference (R) capecitabine tablets was given in randomly allocated sequences TRTR or RTRT (replicate design). Average bioavailability was assessed by ANOVA.
  
  
  RESULTS
  Thirty female and 16 male patients suffering from gastrointestinal or breast cancer (mean age 53.4 years; mean dose 1739 mg) were included. The T/R ratios for AUC0-t(last) and C max were 96.7 % (98 % CI 90.7-103.2 %) and 87.2 % (98 % CI 74.9-101.5 %), respectively. Within-subject variability for AUC0-t(last) and C max (coefficient of variation for R) was 16.5 and 30.2 %, respectively. Similar results were seen for all metabolites. No serious adverse events occurred. For the MTHFR C677T (rs1801133) genotype, an increasing number of 677C alleles showed borderline correlation with an increasing elimination half-life of capecitabine (p = 0.043).
  
  
  CONCLUSIONS
  The extent of absorption was similar for T and R, but the rate of absorption was slightly lower for T. While such differences are not considered as clinically relevant, formal bioequivalence criteria were missed. A possible, probably indirect role of the MTHFR genotype in pharmacokinetics of capecitabine and/or 5-FU should be investigated in further studies.
authors.affiliation: Department of Pharmacology, University of Cologne, Cologne, Germany. christian.queckenberg@uk-koeln.de.|Clinical Trials Centre Cologne, Medical Faculty, University of Cologne, Gleueler Str. 269, 50935, Cologne, Germany. christian.queckenberg@uk-koeln.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Queckenberg
authors.affiliation: Department of Pharmacology, University of Cologne, Cologne, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Erlinghagen
authors.affiliation: Synthon BV, Nijmegen, The Netherlands.
authors.forename: B C M
authors.initials: BC
authors.lastname: Baken
authors.affiliation: Synthon BV, Nijmegen, The Netherlands.
authors.forename: S H G
authors.initials: SH
authors.lastname: Van Os
authors.affiliation: M.A.R.C.O. GmbH & Co. KG, Düsseldorf, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Wargenau
authors.affiliation: Quinta-Analytica S.r.o., Prague, Czech Republic.
authors.forename: V
authors.initials: V
authors.lastname: Kubeš
authors.affiliation: Quinta-Analytica S.r.o., Prague, Czech Republic.
authors.forename: R
authors.initials: R
authors.lastname: Peroutka
authors.affiliation: Quinta-Analytica S.r.o., Prague, Czech Republic.
authors.forename: V
authors.initials: V
authors.lastname: Novotný
authors.affiliation: Department of Pharmacology, University of Cologne, Cologne, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Fuhr
mesh_terms: D065767:Activation, Metabolic / Q000235:genetics*; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000483:Alleles; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D000069287:Capecitabine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D043182:Carboxylesterase / Q000378:metabolism; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000378:metabolism; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics / Q000378:metabolism; D005260:Female; D005467:Floxuridine / Q000378:metabolism; D005472:Fluorouracil / Q000378:metabolism; D005838:Genotype; D006801:Humans; D008099:Liver / Q000201:enzymology; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013607:Tablets; D013810:Therapeutic Equivalency; D013939:Thymidine Phosphorylase / Q000378:metabolism; D013940:Thymidylate Synthase / Q000235:genetics* / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D009363:Neoplasm Proteins; D011355:Prodrugs; D013607:Tablets; D005467:Floxuridine; D003841:Deoxycytidine; D000069287:Capecitabine; C418208:5'-deoxy-5-fluorocytidine; D042943:Dihydrouracil Dehydrogenase (NADP); D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; C543750:TYMP protein, human; D013939:Thymidine Phosphorylase; D043182:Carboxylesterase; D003564:Cytidine Deaminase; D005472:Fluorouracil; C025034:doxifluridine
keywords: Bioequivalence; Capecitabine; Methylenetetrahydrofolate reductase; Pharmacogenetics