Diurnal changes in capecitabine clock-controlled metabolism enzymes are responsible for its pharmacokinetics in male mice

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dc.authorid0000-0002-1734-8340
dc.contributor.authorAkyel, Yasemin Kübra
dc.contributor.authorÖztürk Civelek, Dilek
dc.contributor.authorÖztürk Seyhan, Narin
dc.contributor.authorGül, Şeref
dc.contributor.authorGazioğlu, Işıl
dc.contributor.authorPala Kara, Zeliha
dc.contributor.authorLevi, Francis
dc.contributor.authorKavaklı, İbrahim Halil
dc.contributor.authorOkyar, Alper
dc.date.accessioned2023-04-19T10:47:21Z
dc.date.available2023-04-19T10:47:21Z
dc.date.issued2023
dc.departmentİstanbul Medipol Üniversitesi, Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü, Tıbbi Farmakoloji Ana Bilim Dalı
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 C-max and AUC(0-6h) (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, C-max and AUC(0-6h) 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.description.sponsorshipIstanbul Universityen_US
dc.identifier.citationAkyel, Y. K., Öztürk Civelek, D., Öztürk Seyhan, N., Gül, Ş., Gazioğlu, I., Pala Kara, Z. ... Okyar, A. (2023). Diurnal changes in capecitabine clock-controlled metabolism enzymes are responsible for its pharmacokinetics in male mice. Journal of Biological Rhythms, 38(2), 171-184. https://dx.doi.org/10.1177/07487304221148779
dc.identifier.doi10.1177/07487304221148779
dc.identifier.endpage184
dc.identifier.issn0748-7304
dc.identifier.issn1552-4531
dc.identifier.issue2
dc.identifier.pmid36762608
dc.identifier.scopus2-s2.0-85148107246
dc.identifier.scopusqualityQ2
dc.identifier.startpage171
dc.identifier.urihttps://dx.doi.org/10.1177/07487304221148779
dc.identifier.urihttps://hdl.handle.net/20.500.12511/10884
dc.identifier.volume38
dc.identifier.wos000929446000001en_US
dc.identifier.wosqualityQ2
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorAkyel, Yasemin Kübra
dc.language.isoen
dc.publisherSAGE Publications Inc.
dc.relation.ispartofJournal of Biological Rhythmsen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsAttribution-NonCommercial 4.0 International*
dc.rightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by-nc/4.0/*
dc.subjectCancer
dc.subjectCapecitabine
dc.subjectChronopharmacokinetics
dc.subjectChronotherapy
dc.subjectDiurnal Rhythms
dc.subjectDrug Metabolism
dc.titleDiurnal changes in capecitabine clock-controlled metabolism enzymes are responsible for its pharmacokinetics in male mice
dc.typeArticle

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