Enantiomeric disposition of inhaled, intravenous and oral racemic‐salbutamol in man — no evidence of enantioselective lung metabolism

Abstract

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.

A Comparison of the Expression and Metabolizing Activities of Phase I and II Enzymes in Freshly Isolated Human Lung Parenchymal Cells and Cryopreserved Human Hepatocytes

“…Hydrolysis of BDP to BMP and beclomethasone has been reported in lung homogenates in vitro (Foe et al, 2000) and after administration to human (Daley-Yates et al, 2001). The sulfation of salbutamol has been described previously in lung homogenate in vitro (Pacifici et al, 1996) although this particular pathway was shown not to occur after administration of salbutamol to human (Ward et al, 2000). Interestingly, phase II metabolites of formoterol, a compound known to be sulfated and glucuronidated in human (Rosenborg et al, 1999;Zhang et al, 2002) were not consistently observed in these studies.…”

Determination of the enantiomers of salbutamol and its 4-O-sulphate metabolites in biological matrices by chiral liquid chromatography tandem mass spectrometry

“…Full details of the pharmacokinetic analysis of this study will be reported separately. 40 The LC-MS/MS methods have proved to be robust in their application. The performance of the chiral plasma method is illustrated in Fig.…”

Bioavailability and Bioequivalence

“…Although these drugs are administered by inhalation to the lungs, a significant proportion of the dose is swallowed and subjected to gut first-pass metabolism. In the case of albuterol, enantioselective metabolism of the pharmacologically active (R) antipode indicated preferential bioavailabilty of the (S)-enantiomer from the intestinal tract [117]. In contrast to the higher expression levels of drug-metabolizing enzymes located in the liver, intestinal levels of SULT enzymes have been shown to exceed those of the liver [115].…”