Haematological toxicity following different dosing schedules of 5-fluorouracil and epirubicin in rats.
OBJECTIVE
To study the effects of single and fractionated doses of 5-fluorouracil and epirubicin on the leukocyte counts in rats.


METHODS
Six different dosing patterns of each drug were injected within one day. The leukocytes were followed for 11-15 days. Pharmacokinetic models were developed using NONMEM. Quantitative and qualitative pharmacokinetic-pharmacodynamic relationships were investigated.


RESULTS
A one-compartment model with non-linear elimination described 5-fluorouracil pharmacokinetics and a three-compartment model described epirubicin concentration data. Sigmoidal or basic Emax-models quantified the relationships between individual AUCs and decreases in leukocytes, for both drugs. Similar relationships between AUC and toxicity were found, regardless of whether the drugs were given as single or fractionated doses.


CONCLUSIONS
Quantitative relationships between AUC and the effect on leukocytes were established for 5-fluorouracil and epirubicin. However, no schedule dependence was indicated for the schedules used in the study.
Simonsen
L E
LE
Department of Pharmacy, Uppsala University, Sweden.
Wählby
U
U
Sandström
M
M
Freijs
A
A
Karlsson
M O
MO
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D015251:Epirubicin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D010976:Platelet Count / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D015251:Epirubicin; D005472:Fluorouracil