title: Pharmacokinetics of fluconazole following intravenous and oral administration to koalas (Phascolarctos cinereus).
abstract: 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 (Vss ) were 0.31 (0.11-0.55) L/h/kg and 0.92 (0.38-1.40) L/kg, respectively. The elimination half-life (t1/2 ) 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 (Varea ) displayed an allometric relationship with other mammals, CL and t1/2 did not. Allometrically scaled values were approximately sevenfold lower (CL) and sixfold higher (t1/2 ) than observed values, highlighting flaws associated with this technique in physiologically distinct species. On the basis of fAUC/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.
authors.affiliation: Faculty of Veterinary Science, The University of Sydney, NSW, Australia.
authors.forename: L A
authors.initials: LA
authors.lastname: Black
authors.forename: M B
authors.initials: MB
authors.lastname: Krockenberger
authors.forename: B
authors.initials: B
authors.lastname: Kimble
authors.forename: M
authors.initials: M
authors.lastname: Govendir
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D015725:Fluconazole / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007275:Injections, Intravenous / Q000662:veterinary; D048368:Phascolarctidae / Q000097:blood* / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D015725:Fluconazole