Back to Search
Start Over
Dose tolerability of chronically inhaled voriconazole solution in rodents.
- Source :
-
International journal of pharmaceutics [Int J Pharm] 2009 Sep 08; Vol. 379 (1), pp. 25-31. Date of Electronic Publication: 2009 Jun 11. - Publication Year :
- 2009
-
Abstract
- Invasive pulmonary aspergillosis (IPA) is a fungal disease of the lung associated with high mortality rates in immunosuppressed patients despite treatment. Targeted drug delivery of aqueous voriconazole solutions has been shown in previous studies to produce high tissue and plasma drug concentrations as well as improved survival in a murine model of IPA. In the present study, rats were exposed to 20 min nebulizations of normal saline (control group) or aerosolized aqueous solutions of voriconazole at 15.625 mg (low dose group) or 31.25mg (high dose group). Peak voriconazole concentrations in rat lung tissue and plasma after 3 days of twice daily dosing in the high dose group were 0.85+/-0.63 microg/g wet lung weight and 0.58+/-0.30 microg/mL, with low dose group lung and plasma concentrations of 0.38+/-0.01 microg/g wet lung weight and 0.09+/-0.06 microg/mL, respectively. Trough plasma concentrations were low but demonstrated some drug accumulation over 21 days of inhaled voriconazole administered twice daily. Following multiple inhaled doses, statistically significant but clinically irrelevant abnormalities in laboratory values were observed. Histopathology also revealed an increase in the number of alveolar macrophages but without inflammation or ulceration of the airway, interstitial changes, or edema. Inhaled voriconazole was well tolerated in a rat model of drug inhalation.
- Subjects :
- Administration, Inhalation
Animals
Antifungal Agents administration & dosage
Antifungal Agents adverse effects
Dose-Response Relationship, Drug
Female
Invasive Pulmonary Aspergillosis drug therapy
Macrophages, Alveolar drug effects
Macrophages, Alveolar metabolism
Male
Pyrimidines administration & dosage
Pyrimidines adverse effects
Rats
Rats, Sprague-Dawley
Tissue Distribution
Triazoles administration & dosage
Triazoles adverse effects
Voriconazole
Antifungal Agents pharmacokinetics
Drug Delivery Systems
Lung metabolism
Pyrimidines pharmacokinetics
Triazoles pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1873-3476
- Volume :
- 379
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- International journal of pharmaceutics
- Publication Type :
- Academic Journal
- Accession number :
- 19524030
- Full Text :
- https://doi.org/10.1016/j.ijpharm.2009.06.003