Lung Deposition and Clearance of Inhaled ^99mTc-Heparin in Healthy Volunteers

Abstract

The purpose of this study was to quantify the lower respiratory tract (LRT) dose delivered by a single nebulization of (99m)technetium-labeled sodium heparin as well as its airway distribution, and kinetics of aerosol clearance, since inhaled heparin may be useful in the treatment of asthma. Fifteen healthy subjects (5 male, 10 female) inhaled heparin from a jet nebulizer loaded with 90,000 IU of (99m)Tc-heparin, driving flow rate 10 L/min. Lung scintigrams and blood samples were taken immediately and at several time points up to 24 h after inhalation. 15 +/- 3% (mean +/- SD) (mean 13,300 IU) of the heparin nebulizer charge reached the mouth, and 8 +/- 2% (mean 7,000 IU) was found in the LRT. Jet nebulizer residual was 48 +/- 6% (mean 43,000 IU), 32 +/- 4% (mean 29,000) was found on exhalation filters, and 5 +/- 2% in the tubing. (99m)Tc-heparin was distributed uniformly in the lungs, and clearance was biphasic. 39 +/- 8% of the LRT dose of (99m)Tc-heparin remained in the lungs 24 h after inhalation. 10.00 +/- 3.40% (687 +/- 310 IU) of the LRT dose or 0.76 +/- 0.35% of the nebulizer charge was found in the blood. Peak concentration in the blood was found 61 +/- 25 min after conclusion of inhalation, which took 15 min. We conclude that a small but significant fraction of nebulized heparin reaches the LRT. The inhaled heparin distributes uniformly in the lungs from which it clears slowly, making it suitable for local administration without induction of measurable changes in coagulation assays. Administration of the present single dose of heparin thus appears to be safe.

Effect of inhaled heparin on lung function and coagulation in healthy volunteers

“…It demonstrates that inhalation of ¡32,000 IU of unfractionated heparin as an LRT dose is safe, with respect to pulmonary function and systemic coagulation. To deliver this dose by a Sidestream jet nebulizer driven at a flow rate of 10 L?min -1 requires a nebulizer charge of 400,000 IU heparin, as has been shown in a previous study [11].…”

“…Doses of 100,000, 200,000, 300,000, and 400,000 IU were loaded into one, two, three or four nebulizers. This corresponded to y8,000, 16,000, 24,000, and 32,000 IU of heparin administered to the LRT [11].…”

“…Thus, the estimated LRT dose was highest with the jet nebulizer. Subsequently, it was determined by scintigraphy that 7,000 International Units (IU) were deposited in the LRT after a single nebulization of 90,000 IU of 99m Tc-heparin [11]. In order to investigate the possible use of inhaled heparin in pulmonary disease, the LRT doses must be well defined and quantified, and their effect on the systemic coagulation and on pulmonary function must be known.…”

Suitability of the Upper Airway Models Obtained from MRI Studies in Simulating Drug Lung Deposition from Inhalers

“…As during the MRI studies the subjects were almost inhaled at constant airflow, and the upper airway images only during inhalation were acquired, then applying constant flow through the casts was more appropriate than a sinusoidal flow (10,11). However, the results of this study will overestimate the deposition data that were based on the total amount of the drug that was delivered to the patient (17). This is because part of the inhaled drug was wasted during patient exhalation (17,18).…”

“…However, the results of this study will overestimate the deposition data that were based on the total amount of the drug that was delivered to the patient (17). This is because part of the inhaled drug was wasted during patient exhalation (17,18). Depending on the chosen nebulizer system and drug, 32.36 ± 3.61% (17) and 12.2 ± 3.4% (18) of the nominal dose have been reported to be collected on the exhalation filters.…”