Enantiomeric disposition of inhaled, intravenous and oral racemic‐salbutamol in man — no evidence of enantioselective lung metabolism

• Published in: British journal of clinical pharmacology Vol. 49; no. 1; pp. 15 - 22
• Main Authors: Ward, Jonathan K., Dow, James, Dallow, Nigel, Eynott, Paul, Milleri, Stefano, Ventresca, G. Pietro
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.01.2000; Blackwell Science; Blackwell Science Inc
• Subjects: Administration, Inhalation; Administration, Oral; Adult; Albuterol - administration & dosage; Albuterol - chemistry; Albuterol - pharmacokinetics; Antidotes - pharmacology; Area Under Curve; Biological and medical sciences; Bronchodilator Agents - administration & dosage; Bronchodilator Agents - chemistry; Bronchodilator Agents - pharmacokinetics; Charcoal - pharmacology; Cross-Over Studies; enantiomers; Female; Half-Life; Humans; inhaled; Injections, Intravenous; intravenous; Lung - metabolism; Male; Medical sciences; metabolism; oral; Original; pharmacokinetics; Pharmacology. Drug treatments; rac‐salbutamol; Respiratory system; Stereoisomerism; Human; Agonist; Intravenous administration; Healthy subject; Lung; Oral administration; β2-Adrenergic receptor; Antiasthma agent; Metabolism; Route of administration; Respiratory system; Inhalation; Stereoselectivity; Racemic; Enantiomer; Salbutamol; Pharmacokinetics
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1046/j.1365-2125.2000.00102.x

Aims To establish whether enantioselective metabolism of racemic (rac )‐salbutamol occurs in the lungs by determining its enantiomeric disposition following inhalation, in the absence and presence of oral charcoal, compared with that following the oral and intravenous routes. Methods Fifteen healthy subjects (eight male) were randomized into an open design, crossover study. Plasma and urine salbutamol enantiomer concentrations were measured for 24 h following oral (2 mg) with or without oral charcoal (to block oral absorption), inhaled (MDI; 1200 μg) with or without oral charcoal and intravenous (500 μg) rac‐salbutamol. Systemic exposure (plasma AUC(0,∞) and urinary excretion (Au24h ) of both enantiomers were calculated, and relative exposure to (R)‐salbutamol both in plasma (AUC(R)‐/AUC(S)‐ ) and urine (Au(R)‐/Au(S)‐ ) was derived for each route. Relative exposure after the inhaled with charcoal and oral routes were compared with the intravenous route. Results AUC(R)‐/AUC(S)‐ [geometric mean (95% CI)] was similar following the intravenous [0.32 (0.28, 0.36)] and inhaled with charcoal rates [0.29 (0.24, 0.36); P=0.046], but was far lower following oral dosing [0.05 (0.03, 0.07); P<0.001]. Similar results were found when relative exposure was analysed using Au24h. Conclusions These results show no evidence of significant enantioselective presystemic metabolism in the lungs, whilst confirming it in the gut and systemic circulation, indicating that the (R)‐ and (S)‐enantiomers are present in similar quantities in the airways following inhaled rac‐salbutamol.