The intrapulmonary pharmacokinetics of oral azithromycin were studied in 25 healthy volunteers, each of whom received an initial dose of 500 mg and then 250 mg once daily for four additional doses. Bronchoscopy, bronchoalveolar lavage, and venipuncture were performed 4, 28, 76, 124, 172, 244, 340, and 508 h after the first dose was administered. Azithromycin concentrations in epithelial lining fluid (ELF), alveolar macrophages, peripheral blood monocytes, and serum were measured by high-performance liquid chromatography. Azithromycin was extensively concentrated in cells and ELF. Drug concentrations in AMs (peak mean +/- standard deviation, 464 +/- 65 micrograms/ml) exceeded 80 micrograms/ml up to 508 h (21 days) following the first dose, while concentrations in PBMs (peak, 124 +/- 28 micrograms/ml) exceeded 20 micrograms/ml up to 340 h (14 days). Azithromycin concentrations in ELF peaked at 124 h (3.12 +/- 0.93 micrograms/ml) and were detectable up to 172 h (7 days), when they were 20 times the concurrent serum concentrations. Although the clinical significance of antibiotic concentrations in these compartments is nuclear, the sustained lung tissue penetration and extensive phagocytic accumulation demonstrated in this study support the proven efficacy of azithromycin administered on a 5-day dosage schedule in the treatment of extracellular or intracellular pulmonary infections.

Tests using inhaled particles assess ventilatory nonuniformities and may be sensitive to early changes in the small airways of cigarette smokers. We measured aerosol bolus behavior in 20 asymptomatic smokers and 20 age- and sex-matched nonsmokers for comparison with pulmonary function parameters including the single-breath nitrogen test. Narrow boluses containing 1-micron particles were introduced into 1-I breaths and inhaled to varying lung depths. We examined changes in bolus shape between inhalation and exhalation using plots of aerosol concentration versus respired volume for measurement of bolus dispersion, volumetric change in mean location (mean shift), and quantitative particle deposition. We found exhaled bolus dispersion to be significantly increased in smokers compared with nonsmokers. Volumetric mean shift was significantly different in smokers at shallow lung depths, with the center of bolus mass occurring later in exhalation. FEV1/FVC in smokers was significantly inversely correlated with dispersion at deeper lung depths and with mean shift at all lung depths. Smokers with abnormal spirometry (n = 4) or an abnormal single-breath nitrogen test (n = 7) had significantly increased dispersion compared with smokers with normal pulmonary function tests. We conclude that aerosol bolus dispersion is a useful tool for examination of small airway function in asymptomatic smokers.

The pharmacokinetics of inhaled (R,S)-albuterol following pulmonary absorption were studied in healthy human subjects. Ten subjects (5 females and 5 males) inhaled two puffs (180 microg) of albuterol via a metered-dose inhaler and spacer device. All subjects were nonsmoking and had normal pulmonary function. Charcoal slurries were ingested to block gastrointestinal absorption of drug. Venous samples were obtained from each subject at thirteen time points from 0 through 12 h post dose. (R,S)-Albuterol concentration in plasma was measured using a gas chromatography-mass spectrometry (GC-MS) assay. The plasma concentration-time profiles conformed to a two-compartment extravascular model with first-order absorption kinetics. The drug levels reached maximum in 12.6 +/- 2.2 (SD) minutes, which is in contrast with previous reports that maximum plasma concentrations occur within 2 to 4 h. The mean peak plasma level was 1469 +/- 410 pg/mL. The mean half-life of distribution was 17.9 +/- 8.2 min. The mean half-life of elimination was 4.4 +/- 1.5 h. Female subjects achieved peak concentration more rapidly than male subjects (10.4 vs 14.8 min, p = 0.01) and had a higher mean peak concentration (1778 vs 1159 pg/mL, p = 0.04).

Smokers were given 5 mg of aerosolized nicotine over a 5-min period on 3 separate days to determine if this mode of nicotine delivery could produce nicotine levels similar to those reported from cigarette smoking. Our subjects' mean nicotine level increased from a pretrial level of 12 +/- 2 ng/ml to a peak of 32 +/- 7 ng/ml at 2.5 min after completion of the inhalation. Cough was the most prominent side effect and seemed to be related to irritant effects of the aerosol. Seven of the 16 subjects dropped out of the study because of unpleasant side effects. Side effects did not seem to correlate with nicotine blood levels. We conclude that aerosolized nicotine can produce plasma nicotine levels analogous to cigarette smoking. Cough was a limiting side effect and was presumably due to an irritant effect of the aerosol on the upper airway.