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

Abstract

Aims To assess the absolute bioavailability, pharmacokinetics and metabolism of beclomethasone dipropionate (BDP) in man following intravenous, oral, intranasal and inhaled administration. Methods Twelve healthy subjects participated in this seven-way cross-over study where BDP was administered via the following routes: intravenous infusion (1000 mg), oral (4000 mg, aqueous suspension), intranasal (1344 mg, aqueous nasal spray) and inhaled (1000 mg 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. Results Intravenous administration of BDP (mean CL 150 l h x1 , V ss 20 l, t K 0.5 h) was associated with rapid conversion to B-17-MP which was eliminated more slowly (t 1/2 2.7 h). In estimating the parameters for B-17-MP (mean CL 120 l h x1 , V ss 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, were <1% and 36% (27±47%), respectively. Conclusions 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 insigni®cant. 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.

An evaluation of measured and calculated serum free cortisol in a group of patients with known adrenal suppression

“…beclomethasone dipropionate approximately 3 h). 15 Furthermore, the subjects had not received oral steroids for at least three months prior to the study.…”

Relevance of pharmacokinetics and pharmacodynamics of inhaled corticosteroids to asthma

“…This protein-binding, generally to albumin, is rapid and reversible. The extent of protein-binding ranges 71-99% among currently available ICS (table 3) [21,35,[46][47][48][49][50][51][52][53]66]. The degree of protein-binding of these rapidly metabolised corticosteroids controls their unbound systemic concentrations and limits their systemic side-effects, since only the free drug is pharmacologically active.…”

Towards the bioequivalence of pressurised metered dose inhalers 2. Aerodynamically equivalent particles (with and without glycerol) exhibit different biopharmaceutical profiles in vitro

“…BDP is metabolised to beclomethasone 17-monopropionate (17-BMP), beclomethasone 21-monopropionate (21-BMP) and beclomethasone (BOH). Previous studies have shown that the relative binding affinity of 17-BMP for the cytoplasmic glucocorticoid receptor of human lung is $25 times greater than that of the parent drug BDP [3,20], whereas 21-BMP is practically inactive. The amount of 17-BMP generated and transported in the experiments was proportional to the levels of BDP transported across the cells (Fig.…”