Haematological toxicity following different dosing schedules of 5-fluorouracil and epirubicin in rats

Aim: To study the effects of single and fractionated doses of 5-fluorouraci l and epirubicin on the leukocyte counts in rats. Methods: Six different do sing patterns of each drug were injected within one day. The leukocytes wer e followed for 11-15 days. Pharmacokinetic models were developed using NONM EM. Quantitative and qualitative pharmacokinetic-pharmacodynamic relationsh ips were investigated Results: A one-compartment model with non-lineal elim ination described 5-fluorouracil pharmacokinetics and a three-compartment m odel described epirubicin concentration data. Sigmoidal or basic E-max-mode ls quantified the relationships between individual AUCs and decreases in le ukocytes, for both drugs. Similar relationships between AUC and toxicity we re found, regardless of whether the drugs were given as single or fractiona ted doses. Conclusion: Quantitative relationships between AUC and the effec t on leukocytes were established for 5-fluorouracil and epirubicin. However ; no schedule dependence was indicated for the schedules used in the study.