Single and Multiple Dose Pharmacokinetics of Fluconazole in Loggerhead Sea Turtle (Caretta caretta)
Kate M. Bartlett; Craig A. Harms; Greg A. Lewbart; Mark G. Papich
North Carolina State University, College of Veterinary Medicine, Raleigh,
The pharmacokinetics of the antifungal drug, fluconazole, were studied in
juvenile loggerhead sea turtles (Caretta caretta) following single i.v. and s.c.
injections. Using parameters determined in the single dose study, a multiple-dose s.c. regimen
was then derived and tested.
Pharmacokinetic parameters were calculated, using a two-compartment model,
from plasma concentration-time data obtained following single i.v. and s.c. administrations of
fluconazole at a dose of 2.5 mg/kg body weight in six juvenile sea turtles, using a cross-over
study design. Blood samples were collected at intervals for 120 hours following each single
dose. Plasma fluconazole concentrations were measured by reverse-phase high performance liquid
chromatography. The i.v. and s.c. elimination half-lives were (mean +/- s.d.) 139.5 +/- 36.0
hours and 132.6 +/- 48.7 hours respectively. Systemic clearance of fluconazole was 8.2 +/- 4.3
ml/hr/kg and the apparent volume of distribution was 1.38 +/- 0.29 L/kg. Systemic absorption of
fluconazole after s.c. administration was complete. The derived multiple-dose regimen consisted
of a loading dose of 21 mg/kg body weight and subsequent doses of 10 mg/kg administered via s.c.
injection every 120 hours (5 days). This regimen was administered to four juvenile sea turtles
for 10 days and blood samples were taken to obtain peak and trough plasma concentrations of
fluconazole. Mean peak concentrations were 16.9 +/- 1.1 µg/ml 4 hours after the loading
dose, and 19.1 +/- 2.8 µg/ml 4 hours after the third dose. Mean trough concentrations were
7.2 +/- 2.2 µg/ml 5 days after the first dose, 10.4 +/- 2.7 µg/ml 5 days after the
second dose, and 10.7 +/- 2.9 µg/ml 5 days after the third dose. The terminal half-life was
calculated at 143 hours.
Throughout multiple dosing, fluconazole concentrations remained near or
above 8 µg/ml, a trough concentration of fluconazole targeted when treating human mycotic
infections similar to · fungal pathogens of sea turtles. Results of this study suggest that
fluconazole can be effectively administered to sea turtles at a dose of 10 mg/kg body weight
every 5 days following a loading dose of 21 mg/kg.
This work was supported by the North Carolina Veterinary Medical
Foundation and the Office of the Dean for Research, North Carolina State University, College of
Veterinary Medicine. We thank Jay Barnes and the North Carolina Aquarium at Pine Knoll Shores,
Jean Beasley and the Karen Beasley Sea Turtle Rescue and Rehabilitation Center, Ruth Boettcher
and the North Carolina Wildlife Resources Commission, Cristy Bleck, Elizabeth Chittick, Adrien
Elliott, Bob Jones, Stuart May, Jeff McBane, Kristy McNeal, Delta Plummer, and Rick Schultz for
their help in this study.