Determination of the therapeutic index of floxuridine by its circadian infusion pattern.
To test if circadian timing of a drug is important for its toxicity and antitumor activity, we compared the circadian patterns observed with seven equal doses of floxuridine (FUDR) infused either at a variable rate or at a constant rate in female F344 rats. For the variable-rate infusion, the daily dose of FUDR was divided into four 6-hour portions of 68%, 15%, 2%, and 15% to achieve a quasisinusoidal pattern. Peak drug delivery occurred during one of six different times of day. At a dose level resulting in 50% overall mortality, lethal toxicity differed significantly, depending on the circadian stage of maximum drug delivery. Depending on the circadian stage of maximum drug flow, variable-rate infusions were more toxic than or as toxic as constant-rate infusion. FUDR lethality was lowest when constant-rate infusion was used or when variable-rate infusion peaked during the late activity-early rest span of the recipients. The circadian pattern of variable-rate infusion also determined the antitumor activity in tumor-bearing rats. At a therapeutic dose level and at identical dose intensity, the variable-rate-infusion pattern, with peak drug flow during the late activity-early rest span, resulted in significantly greater delay in tumor growth than was observed with either the constant-rate infusion or other variable-rate patterns. We conclude that the toxicity and antitumor activity of FUDR depend on the circadian timing of the infusion peak when the drug is given by variable-rate infusion. Since some of the circadian-shaped infusions studied are toxicologically and therapeutically inferior to constant-rate infusion, the circadian pattern and not the quasi-intermittency of circadian FUDR administration is primarily responsible for these pharmacodynamic differences.
von Roemeling
R
R
Department of Internal Medicine, Albany Veterans Administration Medical Center, Albany Medical College of Union University, NY 12208.
Hrushesky
W J
WJ
D000230:Adenocarcinoma / Q000188:drug therapy / Q000556:secondary; D000818:Animals; D002940:Circadian Rhythm; D003627:Data Interpretation, Statistical; D004334:Drug Administration Schedule; D005260:Female; D005467:Floxuridine / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity; D007260:Infusion Pumps; D007262:Infusions, Intravenous; D009368:Neoplasm Transplantation; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344
D005467:Floxuridine