Beclomethasone dipropionate: absolute bioavailability, pharmacokinetics and metabolism following intravenous, oral, intranasal and inhaled administration in man

Aims To assess the absolute bioavailability, pharmacokinetics and metabolis m of beclomethasone dipropionate (BDP) in man following intravenous, oral, intranasal and inhaled administration. Methods Twelve healthy subjects participated in this seven-way cross-over s tudy where BDP was administered via the following routes. intravenous infus ion (1000 mug), oral (4000 mug, aqueous suspension), intranasal (1344 mug, aqueous nasal spray) and inhaled (1000 mug ex-valve, metered dose inhaler). The contribution of the lung, nose and gut to the systemic exposure was as sessed by repeating the inhaled, intranasal and oral dosing arms together w ith activated charcoal, to block oral absorption. Blood samples were collec ted for 24 h postdose for the measurement of BDP, beclomethasone-17-monopro pionate (B-17-MP) and beclomethasone (BOH) in plasma by liquid chrornatogra phy tandem mass spectrometry. Results Intravenous administration of BDP (mean CL 150 1 h(-1), V-ss 20 l, t(1/2) 0.5 h) was associated with rapid conversion to B-17-MP which was eli minated more slowly (t(1/2) 2.7 h). In estimating the parameters for B-17-M P (mean CL 120 1 h(-1), V-ss 424 1) complete conversion of BDP to B-17-MP w as assumed. The resultant plasma concentrations of BOH were low and transie nt. BDP was not detected in plasma following oral or intranasal dosing. The mean absolute bioavailability (%F, 90% CI; nominal doses) of inhaled BDP w as 2% (1-4%) and not reduced by coadministration of charcoal. The mean perc entage F of the active metabolite B-17-MP was 41% (31-54%), 44% (34-58%) an d 62% (47-82%) for oral, intranasal and inhaled dosing without charcoal, re spectively. The corresponding estimates of nasal and lung absorption, based on the coadministration of charcoal, were < 1% and 36% (27-47%), respectiv ely. Conclusions Unchanged BDP has negligible oral and intranasal bioavailabilit y with limited absorption following inhaled dosing due to extensive (95%) p resystemic conversion of BDP to B-17-MP in the lung. The oral and intranasa l bioavailabilities of the active metabolite B-17-MP were high and similar, but direct absorption in the nose was insignificant. The total inhaled bio availability of B-17-MP (lung + oral) was also high (62%) and approximately 36% of this nas due to pulmonary absorption. Estimates of oral bioavailabi lity and pulmonary deposition based on total BOH were approximately half th ose found for B-17-MP.