ABSTRACT
Formulation of antibiotics as inhalable products is proposed to improve their therapeutic index when intended for the treatment of pulmonary infections; as vancomycin shows reduced values of lung partition coefficient, pulmonary administration might be an interesting alternative to conventional administration routes. An experimental study has been performed to compare the pulmonary disposition of vancomycin after inhalation of the drug formulated as a solution and as lipid vesicles (conventional liposomes or liposomes modified with chitosan). Vancomycin concentrations were determined in bronchoalveolar fluid, pulmonary tissue and blood samples from 27 Wistar rats distributed in three groups subjected to nebulisation of the drug formulated as a solution, conventional liposomes or chitosomes. Statistically significant differences between the mean drug concentrations in bronchoalveolar lavage (BALF) and lung tissue were found upon comparing the solution to lipid vesicles (116.95 µg ml(-1)±62.13 versus 68.34 µg ml(-1)±28.90 for liposomes and 65.36±22.11 µg g(-1) for chitosomes in BALF; 222.74±37.15 µg g(-1) versus 357.17±65.37 µg g(-1) for liposomes and 378.83±85.87 µg g(-1) for chitosomes in pulmonary tissue). The amount of available drug estimated by mass balance reached the highest values for chitosomes followed by liposomes (24289.66±4795.48 µg and 20207.91±5318.29 µg, respectively) and the lowest for the solution (18971.64±4765.38 µg). The drug transport and tissue uptake processes showed to be dependent on the nebulized formulation, being facilitated by the lipid vesicles that improved drug passage from the airway space to the pulmonary tissue and systemic circulation.
Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Chitosan/chemistry , Drug Delivery Systems , Lung/metabolism , Vancomycin/pharmacokinetics , Administration, Inhalation , Animals , Anti-Bacterial Agents/administration & dosage , Biological Transport , Bronchoalveolar Lavage Fluid/chemistry , Liposomes , Male , Nebulizers and Vaporizers , Rats , Rats, Wistar , Tissue Distribution , Vancomycin/administration & dosageABSTRACT
These days, inhalation constitutes a promising administration route for many drugs. However, this route exhibits unique limitations, and formulations aimed at pulmonary delivery should include as few as possible additives in order to maintain lung functionality. The purpose of this work was to investigate the safety of lactose and chitosan to the pulmonary tissue when delivered by inhalation. The study was carried out with 18 Wistar rats divided in three groups receiving distilled water, lactose or chitosan. A solution of each excipient was administered by inhalation at a dose of 20 mg. The lungs were excised and processed to determine several biochemical parameters used as toxicity biomarkers. Protein and carbonyl group content, lipid peroxidation, reduced and oxidized glutathione (GSSG), myeloperoxidase (MPO), cooper/zinc and manganese superoxide dismutase, catalase, glutathione S-transferase and glutathione peroxidase were determined. Results of myeloperoxidase activity and glutathione disulfide lung concentrations showed a relevant decrease for chitosan group compared to control: 4.67 +/- 2.27 versus 15.10 +/- 7.27 (P = 0.011) for MPO and 0.89 +/- 0.68 versus 2.02 +/- 0.22 (P = 0.014) for GSSG. The other parameters did not vary significantly among groups. Lactose and chitosan administered by inhalation failed to show toxic effects to the pulmonary tissue. A protective effect against oxidative stress might even be attributed to chitosan, since some biomarkers had values significantly lower than those observed in the control group when this product was inhaled. Nevertheless, caution must be taken regarding chemical composition and technological processes applied to incorporate these products during drug formulation, in particular for dry powder inhalators.
Subject(s)
Chitosan/administration & dosage , Chitosan/toxicity , Inhalation Exposure , Lactose/administration & dosage , Lactose/toxicity , Animals , Biocompatible Materials/administration & dosage , Biocompatible Materials/toxicity , Biomarkers/analysis , Drug Administration Routes , Inhalation , Lung/enzymology , Lung/metabolism , Male , Oxidative Stress , Rats , Rats, Wistar , Respiratory Function TestsABSTRACT
Paraquat accumulates in the lung through a characteristic polyamine uptake system. It has been previously shown that paraquat uptake can be significantly prevented if extracellular sodium (Na+) is reduced, although the available data correspond to experiments performed using tissue slices or incubated cells. This type of in vitro study fails to give information on the actual behaviour occurring in vivo since the anatomy and physiology of the studied tissue is disrupted. Accordingly, the aim of the present study was to explore the usefulness of the isolated rat lung model when applied to characterize the kinetic behaviour of paraquat in this tissue after bolus injection under standard experimental conditions as well as to evaluate the influence of iso-osmotic replacement of Na+ by lithium (Li+) in the perfusion medium. The obtained results show that the present isolated rat lung model is useful for the analysis of paraquat toxicokinetics, which is reported herein for the first time. It was also observed that Na+ depletion in the perfusion medium leads to a decreased uptake of paraquat in the isolated rat lung, although it seems that this condition does not contribute to improve the elimination of paraquat once the herbicide reaches the extravascular structures of the tissue, since the paraquat tissue wash-out phase is similar under both experimental conditions assayed.
