Population Pharmacokinetic Model-Based Evaluation of Circadian Variations in Plasma 5-Fluorouracil Concentrations During Long-Term Infusion in Rats: A Comparison With Oral Anticancer Prodrugs

Kobuchi, Shinji; Matsumura, Eisuke; Ito, Yoshiaki; Sakaeda, Toshiyuki

doi:10.1016/j.xphs.2020.04.005

Cited by 3 publications

(3 citation statements)

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“…Studies in humans and animals showed that pharmacokinetics of intravenously administered 5-FU follow a diurnal rhythm (Fleming et al, 2015;Harris et al, 1990;Kobuchi et al, 2016Kobuchi et al, , 2020Kuwahara et al, 2010;Metzger et al, 1994;Petit et al, 1988). The peak concentration of 5-FU occurs in the early rest phase both in laboratory mice and in cancer patients when the drug is infused continuously in a constant rate (Lévi et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2023

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The 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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2023

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“…Recently, the circadian 5-FU patterns in animals were investigated using a PK model with the cosinor method (24)(25)(26)(27) to exclude these potential contributing factors (Figure 1). In rats treated with continuous 5FU infusion (50 mg m -2 h -1 ) for 48 h, PK model analysis showed that the plasma 5-FU concentration followed a 24-h cosine circadian curve, representing an overall 1.8-fold increase from a nadir to a peak, with a relative amplitude (percentage of mesor) of 28% (27). Additionally, the loading bolus dose before initiating the infusion was found to contribute to circadian variations in plasma 5-FU level (27).…”

Section: Pk Model For Evaluating Circadian Variationmentioning

confidence: 99%

“…In rats treated with continuous 5FU infusion (50 mg m -2 h -1 ) for 48 h, PK model analysis showed that the plasma 5-FU concentration followed a 24-h cosine circadian curve, representing an overall 1.8-fold increase from a nadir to a peak, with a relative amplitude (percentage of mesor) of 28% (27). Additionally, the loading bolus dose before initiating the infusion was found to contribute to circadian variations in plasma 5-FU level (27). These observations from animal studies suggest that in the recently modified regimen that omits bolus 5-FU injection, chronomodulation of dosing may enable sufficient clinical response with minimum toxicities and that timing of blood sampling during TDM procedures should be determined cautiously.…”

Section: Pk Model For Evaluating Circadian Variationmentioning

confidence: 99%