Fractional contribution of lung, nasal and gastrointestinal absorption to the systemic level following nose-only aerosol exposure in rats: a case study of 3.7-µm fluorescein aerosols

Abstract

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- micro m fluorescein aerosols at 25.2 micro g/l(air) 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 micro g/kg of simultaneous lung and nasal deposition, respectively, followed by their absorption composing the observed systemic level in this group (AUC(0- infinity ) 137.49 ng/ml h). Thus, assuming linear pharmacokinetics of fluorescein, the extent of absorption (AUC(0- infinity )) due to such nasal deposit (82.5 micro g/kg) was estimated to be 47.00 ng/ml h using the AUC(0- infinity ) obtained in an independent study of intranasal powder insufflation at 34.5 micro g/kg in the charcoal-treated rats (AUC(0- infinity ) 19.66 ng/ml h). As a result, the AUC(0- infinity ) due to 25.7 micro g/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- micro m 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.

In Vitro and In Vivo Lung Deposition of Coated Magnetic Aerosol Particles

“…21 The limit of quantification (LOQ) in lung tissues was 1 ng/mL, and the extraction ratio for the trachea, lung tissue and blood was 0.88, 0.93, and 0.95, respectively.…”

“…20,21 Each lung was weighed and homogenized for 2 min at 08C in 0.5mL of 10mM phosphate buffer (5 mM NaH 2 PO 4 and 5 mM Na 3 PO 4 ). For extraction, 0.2 mL of lung suspension was transferred to a centrifugation tube, and 20 mL of the internal standard 2.5 mg/mL dichlorofluorescein was added.…”

Detection of vesicant-induced upper airway mucosa damage in the hamster cheek pouch model using optical coherence tomography

“…The HMG doses used in those studies ranged from a low of 0.35 mg/animal 22 to a maximum of approximately 4 mg/animal. 17 Based on data from inhalation studies in humans 25 and rats, 26 as well as deposition estimates from "The new ICRP respiratory tract and systemic models," 27 it is reasonable to assume that approximately 3 to 5 times as much HMG is retained in the oral cavity as reaches the lungs. Thus, in order for the directly applied doses to have reached the lungs as a result of inhalation, the amounts retained in the animals' oral cavities in the McClintock et al and Anderson et al studies 17,22 would have been expected to be between 1 mg and 20 mg/animal.…”

Evaluation of the Contribution of the Nasal Cavity and Gastrointestinal Tract to Drug Absorption Following Nasal Application to Rats

“…Sakagami et al 7) investigated fractional contributions of lung, nose, and GI absorption following nose-only aerosol 610 Vol. 30, No.…”

“…Some fraction of nasally administered drug undergoes absorption from the GI tract. Although the contribution of the nose and GI tract to drug absorption after nasal application has been reported, 7) no information on its relation to membrane permeability of the drug is available at present.…”