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Pharmacokinetic and Pharmacodynamic Characteristics and Safety of Inhaled Albuterol Enantiomers in Healthy Volunteers
Author(s) -
GumbhirShah Kavita,
Kellerman Donald J.,
DeGraw Sidney,
Koch Patrick,
Jusko William J.
Publication year - 1998
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/009127009803801203
Subject(s) - pharmacokinetics , bronchodilator , salbutamol , bioavailability , pharmacodynamics , chemistry , crossover study , pharmacology , enantiomer , absorption (acoustics) , racemization , asthma , medicine , stereochemistry , placebo , alternative medicine , physics , pathology , acoustics
The pharmacokinetics and pharmacodynamics of inhaled albuterol given as single or multiple doses of racemate (RS‐) or single enantiomers (R‐, S‐) were determined. In an open‐label, three‐way crossover, parallel‐dose study, 1.25 and 5 mg of (R)‐ and (S)‐albuterol and 2.5 and 10 mg of (RS)‐albuterol were given via nebulization to 15 healthy volunteers. The pharmacokinetic parameters of each enantiomer were determined by noncompartmental and model‐fitting analyses. Both (R)‐ and (S)‐albuterol showed rapid absorption and biexponential decline, with half‐lives (t 1/2 ) averaging 4 and 6 hours, respectively. There were no differences in pharmacokinetics of (R)‐albuterol when administered as (R)‐ or (RS)‐albuterol at the 5‐mg dose with equivalent relative bioavailability as seen from maximum concentration (C max ) and area under the concentration‐time curve (AUC). The same was true for (S)‐albuterol at the 1.25‐mg and 5‐mg doses. The data from 5‐mg doses were considered to be more reliable due to assay sensitivity limitations, and indicated equivalent absorption and disposition of the individual enantiomers. There was no evidence of in vivo racemization, and (R)‐albuterol did not interconvert to (S)‐albuterol. Plasma potassium, plasma glucose, heart rate, and QTc interval were used in linear and E max models to assess responses relating to (R)‐albuterol concentrations. The E max for potassium change was 1.32 meq/L, with an EC 50 of 0.59 and 0.94 ng/mL after administration of (R)‐ and (RS)‐albuterol, respectively. The slopes and intercepts for glucose and heart rate changes were similar after administration of (R)‐ and (RS)‐albuterol. No concentration‐effect relationships were evident for QTc interval or for (S)‐albuterol. The extrapulmonary responses of (R)‐albuterol and adverse effects were similar for single R‐enantiomer or the racemic mixture .