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.