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

Abstract

Circadian fluctuations in the plasma concentration of 5-fluorouracil impede the accurate estimation of target therapeutic concentrations in the long-term infusion or oral 5-fluorouracil-based prodrug regimen. We evaluated the circadian patterns of plasma 5-fluorouracil concentrations in rats using population pharmacokinetic model. Rats were divided into 2 groups, and a continuous infusion (50 mg/m2/h) for 48 h was initiated with or without a bolus injection of 60 mg/kg 5-fluorouracil. In the group not administered a loading dose, significant circadian variation of plasma 5-fluorouracil concentration was observed. In contrast, in the loading dose group, this circadian variation disappeared. Additionally, decreased hepatic dihydropyrimidine dehydrogenase activity was observed. Population model analysis revealed that the concentrations of 5-fluorouracil followed a 24-h cosine circadian curve, representing an overall 1.8-fold increase from a nadir to a peak, with a relative amplitude (% of mesor) of 28%. The circadian 5-fluorouracil clearance pattern in the infusion-regimen was consistent with previously reported pattern for capecitabine and uracil-tegafur. In the recently modified regimen omitting the bolus injection of 5-fluorouracil, the circadian variations should be considered for blood sampling time points in therapeutic drug monitoring. The chronomodulated chemotherapy using oral prodrug administration could be established based on accumulating evidence in the infusion-regimen.