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To assess the absolute bioavailability, pharmacokinetics and metabolism of beclomethasone dipropionate (BDP) in man following intravenous, oral, intranasal and inhaled administration.Twelve healthy subjects participated in this seven-way cross-over study where BDP was administered via the following routes: intravenous infusion (1000 microg), oral (4000 microg, aqueous suspension), intranasal (1344 microg, aqueous nasal spray) and inhaled (1000 microg ex-valve, metered dose inhaler). The contribution of the lung, nose and gut to the systemic exposure was assessed by repeating the inhaled, intranasal and oral dosing arms together with activated charcoal, to block oral absorption. Blood samples were collected for 24 h postdose for the measurement of BDP, beclomethasone-17-monopropionate (B-17-MP) and beclomethasone (BOH) in plasma by liquid chromatography tandem mass spectrometry.Intravenous administration of BDP (mean CL 150 l h-1, Vss 20 l, t(1/2) 0.5 h) was associated with rapid conversion to B-17-MP which was eliminated more slowly (t1/2 2.7 h). In estimating the parameters for B-17-MP (mean CL 120 l h-1, Vss 424 l) complete conversion of BDP to B-17-MP was assumed. The resultant plasma concentrations of BOH were low and transient. BDP was not detected in plasma following oral or intranasal dosing. The mean absolute bioavailability (%F, 90% CI; nominal doses) of inhaled BDP was 2% (1-4%) and not reduced by coadministration of charcoal. The mean percentage F of the active metabolite B-17-MP was 41% (31-54%), 44% (34-58%) and 62% (47-82%) for oral, intranasal and inhaled dosing without charcoal, respectively. The corresponding estimates of nasal and lung absorption, based on the coadministration of charcoal, were1% and 36% (27-47%), respectively.Unchanged BDP has negligible oral and intranasal bioavailability with limited absorption following inhaled dosing due to extensive (95%) presystemic conversion of BDP to B-17-MP in the lung. The oral and intranasal bioavailabilities of the active metabolite B-17-MP were high and similar, but direct absorption in the nose was insignificant. The total inhaled bioavailability of B-17-MP (lung + oral) was also high (62%) and approximately 36% of this was due to pulmonary absorption. Estimates of oral bioavailability and pulmonary deposition based on total BOH were approximately half those found for B-17-MP.

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 microg) with or without oral charcoal and intravenous (500 microg) rac-salbutamol. Systemic exposure (plasma AUC(0,infinity) 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); P0.001]. 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.