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Diurnal Changes in Capecitabine Clock-Controlled Metabolism Enzymes Are Responsible for Its Pharmacokinetics in Male Mice

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dc.contributor.authorAkyel Y. K.
dc.contributor.authorÖztürk Civelek D.
dc.contributor.authorOzturk Seyhan N.
dc.contributor.authorGul S.
dc.contributor.authorGazioglu I.
dc.contributor.authorPala Kara Z.
dc.contributor.authorLévi F.
dc.contributor.authorKavakli I. H.
dc.contributor.authorOkyar A.
dc.contributor.institutionauthorÖZTÜRK CİVELEK, DİLEK
dc.date.accessioned2023-02-19T21:30:11Z
dc.date.available2023-02-19T21:30:11Z
dc.date.issued2023-02-01
dc.description.abstractThe circadian timing system controls absorption, distribution, metabolism, and elimination processes of drug pharmacokinetics over a 24-h period. Exposure of target tissues to the active form of the drug and cytotoxicity display variations depending on the chronopharmacokinetics. For anticancer drugs with narrow therapeutic ranges and dose-limiting side effects, it is particularly important to know the temporal changes in pharmacokinetics. A previous study indicated that pharmacokinetic profile of capecitabine was different depending on dosing time in rat. However, it is not known how such difference is attributed with respect to diurnal rhythm. Therefore, in this study, we evaluated capecitabine-metabolizing enzymes in a diurnal rhythm-dependent manner. To this end, C57BL/6J male mice were orally treated with 500 mg/kg capecitabine at ZT1, ZT7, ZT13, or ZT19. We then determined pharmacokinetics of capecitabine and its metabolites, 5′-deoxy-5-fluorocytidine (5′DFCR), 5′-deoxy-5-fluorouridine (5′DFUR), 5-fluorouracil (5-FU), in plasma and liver. Results revealed that plasma Cmax and AUC0-6h (area under the plasma concentration-time curve from 0 to 6 h) values of capecitabine, 5′DFUR, and 5-FU were higher during the rest phase (ZT1 and ZT7) than the activity phase (ZT13 and ZT19) ( p < 0.05). Similarly, Cmax and AUC0-6h values of 5′DFUR and 5-FU in liver were higher during the rest phase than activity phase ( p < 0.05), while there was no significant difference in liver concentrations of capecitabine and 5′DFCR. We determined the level of the enzymes responsible for the conversion of capecitabine and its metabolites at each ZT. Results indicated the levels of carboxylesterase 1 and 2, cytidine deaminase, uridine phosphorylase 2, and dihydropyrimidine dehydrogenase ( p < 0.05) are being rhythmically regulated and, in turn, attributed different pharmacokinetics profiles of capecitabine and its metabolism. This study highlights the importance of capecitabine administration time to increase the efficacy with minimum adverse effects.
dc.identifier.citationAkyel Y. K., Öztürk Civelek D., Ozturk Seyhan N., Gul S., Gazioglu I., Pala Kara Z., Lévi F., Kavakli I. H., Okyar A., "Diurnal Changes in Capecitabine Clock-Controlled Metabolism Enzymes Are Responsible for Its Pharmacokinetics in Male Mice", JOURNAL OF BIOLOGICAL RHYTHMS, cilt.7487304221148779, sa.0, 2023
dc.identifier.doi10.1177/07487304221148779
dc.identifier.issn0748-7304
dc.identifier.issue0
dc.identifier.pubmed36762608
dc.identifier.urihttp://journals.sagepub.com/doi/pdf/10.1177/07487304221148779
dc.identifier.urihttps://hdl.handle.net/20.500.12645/37083
dc.identifier.volume7487304221148779
dc.relation.ispartofJOURNAL OF BIOLOGICAL RHYTHMS
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectEczacılık
dc.subjectMeslek Bilimleri
dc.subjectFarmakoloji
dc.subjectSağlık Bilimleri
dc.subjectPharmacology and Therapeutics
dc.subjectProfessional Sciences
dc.subjectPharmacology
dc.subjectHealth Sciences
dc.subjectKlinik Tıp (MED)
dc.subjectYaşam Bilimleri (LIFE)
dc.subjectFarmakoloji ve Toksikoloji
dc.subjectFARMAKOLOJİ VE ECZACILIK
dc.subjectClinical Medicine (MED)
dc.subjectLife Sciences (LIFE)
dc.subjectPHARMACOLOGY & TOXICOLOGY
dc.subjectPHARMACOLOGY & PHARMACY
dc.subjectFarmakoloji, Toksikoloji ve Eczacılık (çeşitli)
dc.subjectGenel Farmakoloji, Toksikoloji ve Eczacılık
dc.subjectFarmakoloji (tıbbi)
dc.subjectİlaç Rehberleri
dc.subjectYaşam Bilimleri
dc.subjectPharmacy
dc.subjectPharmacology, Toxicology and Pharmaceutics (miscellaneous)
dc.subjectGeneral Pharmacology, Toxicology and Pharmaceutics
dc.subjectPharmacology (medical)
dc.subjectDrug Guides
dc.subjectLife Sciences
dc.titleDiurnal Changes in Capecitabine Clock-Controlled Metabolism Enzymes Are Responsible for Its Pharmacokinetics in Male Mice
dc.typearticle
dspace.entity.typePublication
local.avesis.idd63440e1-0956-455c-9c0d-99922c10ace2
relation.isAuthorOfPublication821c461c-752b-4a78-a2e5-a6aaf5076b88
relation.isAuthorOfPublication.latestForDiscovery821c461c-752b-4a78-a2e5-a6aaf5076b88
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