Application of a radioreceptor assay in a pharmacokinetic study of oxitropium bromide in healthy volunteers after single i.v., oral and inhalation doses

Summary

Oxitropium bromide (OXBR) is a new anticholinergic drug, which is expected to be useful in the treatment of nocturnal asthma. The only pharmacokinetic data were obtained with the¹⁴C-labelled compound. A sensitive radioreceptor assay for the determination of unlabelled OXBR in plasma was developed, based on competition between OXBR and³H-N-methylscopolamine for binding to muscarinic receptors. OXBR was isolated from plasma by ion-pair extraction and re-extraction. Active metabolites present in significant amounts might interfere in the assay, but this was not the case for OXBR metabolites. Detection limits were 300 pg·ml⁻¹ and 3 ng·ml⁻¹ for plasma and urine, respectively. For the latter no extraction step was required. The single dose pharmacokinetics of OXBR was studied following inhalation (3 mg), oral (2 mg) and i.v. (1 mg) administration to 12 men, following an open, cross-over design.

After i.v. administration the kinetic parameters were: V_c 38.4 l; t_1/2α 5.3 min; t_1/2β 142 min; AUC 8.9 h·ng·ml⁻¹; renal excretion 50.2%, k₁₀ 3.5 l·h⁻¹ and total clearance 1874 ml/min. The apparent bioavailabilities were 0.48% and 12.4% by the oral and inhalation routes, respectively, based on the cumulative renal excretion. There were moderate adverse reactions due to the anticholinergic properties of the drug.