| Abstrakt: |
Because absorption takes place from multiple sites of aerosol deposition, it is generally difficult to interpret systemic levels following nose-only inhalation in laboratory rodents. Therefore, this study attempted to determine the fractional contribution of lung, nasal and gastrointestinal (GI) absorption to the observed systemic level following nose-only aerosol exposure in rats using fluorescein as a model powder solute. Rats were treated orally with vehicle or activated charcoal, the latter diminishing GI absorption of fluorescein, and were subsequently nose-only exposed to 3.7-µm fluorescein aerosols at 25.2 µg/lair for 10 min. While fluorescein similarly disappeared from the lung at a half-life of 0.23 hr, its plasma concentrations in the charcoal-treated group were significantly lower than those in the charcoal-untreated (vehicle) group. This suggests that significant portions of fluorescein were transported by nasopharyngeal and tracheobronchial mucociliary clearances following aerosol exposure and were absorbed from the GI tract. Despite the lack of GI absorption in the charcoal-treated animals, it was estimated that this nose-only exposure of fluorescein allowed 25.7 and 82.5 µg/kg of simultaneous lung and nasal deposition, respectively, followed by their absorption composing the observed systemic level in this group (AUC0–∞ 137.49 ng/ml h). Thus, assuming linear pharmacokinetics of fluorescein, the extent of absorption (AUC0–∞) due to such nasal deposit (82.5 µg/kg) was estimated to be 47.00 ng/ml h using the AUC0–∞ obtained in an independent study of intranasal powder insufflation at 34.5 µg/kg in the charcoal-treated rats (AUC0–∞ 19.66 ng/ml h). As a result, the AUC0–∞ due to 25.7 µg/kg of the lung deposit was deconvoluted to be 90.49 ng/ml h and finally, the absolute bioavailability (F%) of the "lung-region-specific" deposition and absorption of fluorescein was estimated to be 55.0%. It is observed therefore, that lung, nasal and GI absorption accounted for 24.2, 12.5 and 63.3% of the total fluorescein absorption, respectively, following nose-only exposure of 3.7-µm aerosols. This study addresses the common methodological insufficiency of nose-only inhalation studies in rodents, which have been neglected in most cases, and provides the appropriate kinetic interpretation for their observed systemic level. [ABSTRACT FROM AUTHOR] |
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