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Pharmacokinetics of fluconazole following intravenous and oral administration to koalas ( Phascolarctos cinereus )
Author(s) -
Black L. A.,
Krockenberger M. B.,
Kimble B.,
Govendir M.
Publication year - 2014
Publication title -
journal of veterinary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.527
H-Index - 60
eISSN - 1365-2885
pISSN - 0140-7783
DOI - 10.1111/jvp.12072
Subject(s) - fluconazole , cryptococcus gattii , pharmacokinetics , bioavailability , volume of distribution , phascolarctos cinereus , pharmacology , oral administration , plasma clearance , absorption (acoustics) , chemistry , distribution (mathematics) , pharmacodynamics , medicine , antifungal , cryptococcosis , immunology , population , mathematical analysis , physics , mathematics , environmental health , dermatology , acoustics
Clinically normal koalas ( n = 12) received a single dose of 10 mg/kg fluconazole orally (p.o.; n = 6) or intravenously (i.v.; n = 6). Serial plasma samples were collected over 24 h, and fluconazole concentrations were determined using a validated HPLC assay. A noncompartmental pharmacokinetic analysis was performed. Following i.v. administration, median (range) plasma clearance (CL) and steady‐state volume of distribution ( V ss ) were 0.31 (0.11–0.55) L/h/kg and 0.92 (0.38–1.40) L/kg, respectively. The elimination half‐life ( t 1/2 ) was much shorter than in many species (i.v.: median 2.25, range 0.98–6.51 h; p.o.: 4.69, range 2.47–8.01 h), and oral bioavailability was low and variable (median 0.53, range 0.20–0.97). Absorption rate‐limited disposition was evident. Plasma protein binding was 39.5 ± 3.5%. Although fluconazole volume of distribution ( V area ) displayed an allometric relationship with other mammals, CL and t 1/2 did not. Allometrically scaled values were approximately sevenfold lower (CL) and sixfold higher ( t 1/2 ) than observed values, highlighting flaws associated with this technique in physiologically distinct species. On the basis of f AUC /MIC pharmacodynamic targets, fluconazole is predicted to be ineffective against Cryptococcus gattii in the koala as a sole therapeutic agent administered at 10 mg/kg p.o. every 12 h.