We developed a flow-limited physiologically based pharmacokinetic model for residues of monensin in chickens and evaluated its predictive ability by comparing it with an external data set describing concentration decays after the end of treatment. One advantage of this model is that the values for most parameters (34 of 38) were taken directly from the literature or from field data (for growth and feed intake). Our model included growth (changes in body weight) to describe exposure throughout the life of the chicken. We carried out a local sensitivity analysis to evaluate the relative importance of model parameters on model outputs and revealed the predominant influence of 19 parameters (including three estimated ones): seven pharmacokinetic parameters, five physiological parameters and seven animal performance parameters. Our model estimated the relative bioavailability of monensin as feed additive at 3.9%, which is even lower than the absolute bioavailability in solution (29.91%). Our model can be used for extrapolations of farming conditions, such as monensin supplementation or building lighting programme (which may have a significant impact for short half-life molecules such as monensin). This validated PBPK model may also be useful for interspecies extrapolations or withdrawal period calculations for modified dosage regimens.
The aim of this study was to investigate the pharmacokinetics of oseltamivir phosphate, a prodrug, and its active moiety in plasma and lung after its nebulization and intravenous administration in rats. Only 2% of prodrug was converted into active moiety presystematically, attesting to a low advantage of oseltamivir phosphate nebulization, suggesting that oseltamivir phosphate nebulization is not a good option to obtain a high exposure of the active moiety at the infection site within lung.A recent series of studies conducted in our laboratory (1-6) has shown that membrane permeability is a key parameter to support drug nebulization (NEB) for local efficacy enhancement. From a biopharmaceutical standpoint, antimicrobial agents for parenteral administration, such as aminoglycosides, are much better candidates for NEB due to their limited membrane permeability (4) than those with high membrane permeability, allowing oral administration, such as fluoroquinolones (2). We have also shown that the antiinfluenza drug oseltamivir carboxylate (OC) could be a good candidate for nebulization (1), and we hypothesize now that its orally administered prodrug, oseltamivir phosphate (OP), is not. The aim of this study was to confirm this hypothesis.In vitro permeability experiments were performed in Calu-3 cell line with determination of the apparent permeability (Papp) (7). Briefly, OP and OC (Sigma, Saint Quentin Fallavier, France; AlsaChimand, Illkirch-Graffenstaden, France) solutions were used at 0.250 and 1 g/ml, respectively, for both apical-basolateral (AP/BL) and basolateral-apical (BL/AP) studies. Samples (150 l) were taken at various times in each compartment in function of the studied direction. The in vivo study was authorized by the ethics committee COMETHEA and registered by the French Ministry of Higher Education and Research (no. 2015070211159865). Forty male Sprague Dawley rats (300 to 330 g; Charles River, l'Arbresle, France) were divided in two groups (n ϭ 20; intravenous [i.v.] or intratracheal [i.t.]). OP solution was administered at a dose of 6 mg/kg by i.v. bolus (1 ml) through the tail vein or by i.t. administration (100 l) using a nebulizer (Microsprayer 1A-1B; PennCentury, Inc., Wyndmoor, PA) (8). Bronchoalveolar lavage (BAL) and blood samples were collected until 6 h postadministration (five rats per sampling time). Dichlorvos (4 mg/ml in 0.9% saline solution [5%, vol/vol]; Sigma) was added to samples. BAL and plasma samples were frozen at -80°C until analysis. OP and OC concentrations were determined by liquid chromatography-tandem mass spectrometry according to the method of Gupta et al. (9) using a system that included a Shimadzu HPLC module (Nexera XR; Shimadzu, Marne-la-Vallée, France) coupled with a API 3000 mass
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