Pulmonary Pharmacokinetics of Oseltamivir Carboxylate in Rats after Nebulization or Intravenous Administration of Its Prodrug, Oseltamivir Phosphate

Abstract

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

Treatment of respiratory viral infections through inhalation therapeutics: Challenges and opportunities

“…However, only 2% of OP prodrug get converted into active form pre-systematically, confirming the low benefit of OP nebulization. Therefore, it was suggested that pulmonary administration of OP may not be a good choice to get a high concentration of its active form at the infection site of the lung [ 34 ]. Extensive clinical studies are required to explore the application of respiratory administration of OP.…”