Pharmacokinetics of (R,S)-Albuterol after Aerosol Inhalation in Healthy Adult Volunteers PAULA J. ANDERSON,* XIANG ZHOU,PHIL BREEN,LARRY GANN,TODD W. LOGSDON,CESAR M. COMPADRE, AND F. CHARLES HILLER Contribution from Division of Pulmonary and Critical Care Medicine and Departments of Biopharmaceutical Sciences and Pharmaceutics, University of Arkansas for Medical Sciences and John L. McClellan Veterans Administration Hospital, Little Rock, Arkansas 72205. Received November 24, 1997. Final revised manuscript received March 30, 1998. Accepted for publication March 31, 1998. Abstract 0 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 µg) 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). Introduction Albuterol (Figure 1a) is a  2 -adrenergic agonist that has been widely used as an inhaled medication for the treat- ment of asthma and chronic obstructive lung disease. Inhaled  2 -agonists are advantageous because drug is delivered to the site of desired action in the airways and systemic side effects are minimized. Because of the small administered dose, plasma levels of albuterol after inhala- tion are low and require a sensitive assay for measurement. Moreover, the relationship of plasma drug levels to pul- monary drug levels and clinical response is not known. Different aspects of the pharmacokinetics of inhaled al- buterol in healthy volunteers 1-4 and in asthmatic 5-7 and cystic fibrosis patients 8 have been described. Many of the previous pharmacokinetic and pharmacodynamic studies have been limited by the sensitivity of the assays employed. Most of the available data have been measured after inhalation of doses of albuterol far in excess of that necessary to cause bronchodilation. When albuterol is administered via metered-dose in- haler, only about 10% of the dose is deposited in the lungs. 9 Approximately 80% of the dose is deposited in the orophar- ynx with systemic absorption occurring locally or via the gastrointestinal tract after swallowing. For albuterol, between 40 and 50% of swallowed drug will appear in the plasma 10 and the contribution of this portion of the dose to clinical efficacy and toxicity is not known. Most previous pharmacokinetic studies were not designed to block gas- trointestinal tract absorption and so may not accurately reflect pharmacokinetics after lower respiratory tract drug uptake. Some investigators have approached this problem by using a urine sample at 30 min post albuterol dose as a measure of the relative bioavailability of albuterol to the lungs. 11,12 Other investigators have studied pulmonary absorption of inhaled bronchodilators by blocking gas- trointestinal absorption with slurries of activated char- coal. 13 A common clinical practice used to decrease the amount of drug delivered to the oropharynx is the addition of a spacer device or holding chamber to the metered dose inhaler. 14 With improvements in drug delivery systems for inhaled drugs, less of the plasma level of albuterol is due to the swallowed drug, thus it is important to characterize the absorption and disposition of drug delivered to the lungs. Because of the lack of a sensitive assay for albuterol, there is little information about the pharmacokinetics of albuterol absorbed from the lungs and the relationship to clinical efficacy. We have developed a sensitive GC/MS assay for determination of plasma (R,S)-albuterol levels down to the picogram range after inhalation. 15 In this report, we examined the pharmacokinetics of albuterol in healthy subjects following inhalation of a clinically relevant dose from a metered-dose inhaler with absorption limited to the pulmonary route. Materials and Methods SubjectssTen healthy nonsmoking volunteers were studied. Subjects included 5 females and 5 males; mean age was 26 ((3 SD) years. Mean mass for males was 78 ((8 SD) kg and for * Corresponding author: Paula J. Anderson, M. D. Division of Pulmonary and Critical Care Medicine University of Arkansas for Medical Sciences 4301 W. Markham, Slot 555, Little Rock, AR 72205. Tel: (501) 686-5525. Fax: (501) 686-7893. Email: PaulaAnderson@ exchange.uams.edu. Figure 1sChemical structures of albuterol (a) and [ 13 C]albuterol (b). © 1998, American Chemical Society and S0022-3549(97)00445-0 CCC: $15.00 Journal of Pharmaceutical Sciences / 841 American Pharmaceutical Association Vol. 87, No. 7, July 1998 Published on Web 05/13/1998