Pharmacokinetics and tolerance of repeated oral administration of 5-fluorocytosine in healthy dogs

BMC Veterinary Research

Eve Laloy¹  Christelle Maurey²  Frédérique Degorce³  Baptiste Moreau⁴  Philippe Erbs⁴  Éric Quéméneur⁴  Matthias Kohlhauer⁵  Bernard Klonjkowski⁶  Jérémy Béguin⁶ 

[1] Anatomical Pathology Unit;Department of Internal Medicine, École Nationale Vétérinaire d’Alfort, ANSES, Université Paris-Est;Laboratoire d’Anatomie Pathologique Vétérinaire du Sud-Ouest;Transgene;U955 - IMRB Inserm, École Nationale Vétérinaire d’Alfort, UPEC;UMR Virologie, INRAE, École Nationale Vétérinaire d’Alfort, ANSES, Université Paris-Est;

关键词: Flucytosine;    Fluorouracil;    Drug-related side effects;    Adverse reactions;    Pharmacokinetic;    Dog;   

DOI  :  10.1186/s12917-021-02927-5

来源: DOAJ

【 摘 要 】

Abstract Background 5-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. Results In 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. Conclusions Long 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.

【 授权许可】

Unknown