PURPOSE: 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.
- MeSH
- alely MeSH
- antimetabolity antitumorózní aplikace a dávkování farmakokinetika MeSH
- aplikace orální MeSH
- capecitabinum aplikace a dávkování farmakokinetika MeSH
- cytidindeaminasa genetika metabolismus MeSH
- deoxycytidin analogy a deriváty metabolismus MeSH
- dihydrouracildehydrogenasa (NADP) genetika metabolismus MeSH
- dospělí MeSH
- floxuridin metabolismus MeSH
- fluorouracil metabolismus MeSH
- genotyp MeSH
- játra enzymologie MeSH
- jednonukleotidový polymorfismus MeSH
- karboxylesterasa metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- metabolická aktivace genetika MeSH
- methylentetrahydrofolátreduktasa (NADPH2) genetika metabolismus MeSH
- nádorové proteiny metabolismus MeSH
- plocha pod křivkou MeSH
- prekurzory léčiv aplikace a dávkování farmakokinetika MeSH
- senioři MeSH
- tablety MeSH
- terapeutická ekvivalence MeSH
- thymidinfosforylasa metabolismus MeSH
- thymidylátsynthasa genetika metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- srovnávací studie MeSH
