Abstract
Background5-fluorocytosine is a pyrimidine and a fluorinated cytosine analog mainly used as an antifungal agent. It is a precursor of 5-fluorouracil, which possesses anticancer properties. To reduce systemic toxicity of 5-fluorouracil during chemotherapy, 5- fluorocytosine can be used as a targeted anticancer agent. Expression of cytosine deaminase by a viral vector within a tumor allows targeted chemotherapy by converting 5-fluorocytosine into the cytotoxic chemotherapeutic agent 5-fluorouracil. However, little is known about the tolerance of 5-fluorocytosine in dogs after prolonged administration.ResultsIn three healthy Beagle dogs receiving 100 mg/kg of 5-fluorocytosine twice daily for 14 days by oral route, non-compartmental pharmacokinetics revealed a terminal elimination half-life of 164.5 ± 22.5 min at day 1 and of 179.2 ± 11.5 min, after 7 days of administration. Clearance was significantly decreased between day 1 and day 7 with 0.386 ± 0.031 and 0.322 ± 0.027 ml/min/kg, respectively. Maximal plasma concentration values were below 100 µg/ml, which is considered within the therapeutic margin for human patients. 5-fluorouracil plasma concentration was below the limit of detection at all time points. The main adverse events consisted of depigmented, ulcerated, exudative, and crusty cutaneous lesions 10 to 13 days after beginning 5-fluorocytosine administration. The lesions were localized to the nasal planum, the lips, the eyelids, and the scrotum. Histological analyses were consistent with a cutaneous lupoid drug reaction. Complete healing was observed 15 to 21 days after cessation of 5-fluorocytosine. No biochemical or hematological adverse events were noticed.ConclusionsLong term administration of 5-fluorocytosine was associated with cutaneous toxicity in healthy dogs. It suggests that pharmacotherapy should be adjusted to reduce the toxicity of 5-fluorocytosine in targeted chemotherapy.
Highlights
MethodsLaboratory dogs Two female and one male adult healthy Beagle dogs (Harlan Laboratories, Gannat, France) were used
This study describes pharmacokinetics and tolerance of repeated oral administration of 5-FC at 100 mg/kg in three healthy dogs, and has not been previously described in dogs
All animals were fasted 12 h before 5-FC administration and food intake is probably not interacting with the pharmacokinetics of 5-FC
Summary
Laboratory dogs Two female and one male adult healthy Beagle dogs (Harlan Laboratories, Gannat, France) were used. The weight of the dog was between 11.0 and 16.9 kg. All dogs were acclimatized for seven days before starting the experiment and were under the care of a licensed veterinarian. The dogs were housed individually in stainlees-steel bar boxes with a resin soil substrate and a shaved softwood litter. The room temperature was 19 °C (+/- 2 °C) with a humidity greater than 35 %, and the day/night cycle was 12:12 h. Dogs were fed twice daily with a certified commercial canine diet and given potable water ad libitum. Dogs were not euthanized at the end of the study. All the dogs that participated were rehomed as companion animals one month after the end of the study
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