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 mg ) with or without oral charcoal and intravenous (500 mg) rac-salbutamol. Systemic exposure ( plasma AUC(0,2) and urinary excretion (Au 24h ) 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. Similar results were found when relative exposure was analysed using Au 24h . 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.

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1 Fluticasone propionate ( FP) is a potent glucocorticoid used in the treatment of asthma. Prior to reporting the pharmacokinetics following the inhaled and oral routes, the pharmacokinetics need to be established following intravenous dosing. The present study determines the intravenous pharmacokinetics of FP, using non-compartmental analysis, in healthy male subjects over the 250 to 1000mg dose range. 2 The pharmacokinetics of FP can be regarded as being linear over this dosing range. FP was extensively distributed within the body (V ss 318 l ), rapidly cleared (CL 1.1 l min−1) with a terminal elimination half-life of 7.8 h and a mean residence time of 4.9 h. 3 In order that future pharmacokinetic/pharmacodynamic and other modelling can be carried out, the plasma concentration-time profiles were parameterized using a model based on sums of exponentials, the appropriateness of this model was justified as the secondary kinetic parameters from the model were similar to those obtained using non-compartmental analysis.Keywords glucocorticosteroid fluticasone propionate pharmacokinetics healthy subjects intravenous Introduction Preliminary pharmacokinetics of intravenous FP (2000mg dose) were investigated early in the drug's development [4 ]. However, in recent years the assay's Fluticasone propionate (FP) is a highly potent lipophilic glucocorticoid which was designed to be metabolically lower limit of quantification has been improved from 0.13 ng ml−1 to 0.05 ng ml−1 along with its precision and labile and have a low oral bioavailability thus minimizing systemic effects e.g. reductions in plasma cortisol. Studies accuracy. The present paper reports the intravenous pharmacokinetics of FP in healthy male subjects over in rats and mice have shown FP to have a high topical to systemic activity ratio [1]. In clinical studies FP has the 250 to 1000mg dose range from five clinical studies. been found to be topically effective in the treatment of asthma and allergic rhinitis [2], where the maximum single inhaled dose is 1000mg day−1.The pharmacokinetic parameters of FP need to be Methods established following intravenous dosing, this is important for simulations and pharmacokinetic/pharmacoStudy design dynamic modelling purposes. The present study will establish whether the distribution and elimination proStudy 1 Twelve healthy male volunteers, mean age 28 years (range 21-38 years) and mean weight 75kg (range cesses of FP in the systemic circulation are linear. Therefore, any non-linearity observed following either 55-100kg) received in a double-blind cross-over study, single doses of 250, 500 and 1000mg intravenous FP as the oral or inhaled routes of administration must be attributed to some other process than distribution and 3 min infusions. elimination. The inhaled bioavailability following a metered dose inhaler is approximately 26% and the Studies 2-5 In total, 48 healthy male volunteers (12 subjects in each study), mean age 23 years (range 18-42 average oral bioavailability is less than 1% [3 ].

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These results in healthy subjects indicate that there is no systemic pharmacodynamic or pharmacokinetic interaction between inhaled salmeterol and fluticasone propionate when given in combination.