1. Chiral investigation of midodrine, a long-acting alpha-adrenergic stimulating agent
- Author
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Quaglia, Maria Giovanna, Farina, A., Palmery, Maura, Desideri, Nicoletta, Donati, E., Bossu', E., and Strano, Stefano
- Subjects
deglymidodrine ,Dose-Response Relationship, Drug ,Hydrolysis ,Electrophoresis, Capillary ,Aorta, Thoracic ,Stereoisomerism ,chiral chromatography ,midodrine ,pure enantiomer ,racemates ,Carbon ,Midodrine ,Models, Chemical ,Animals ,Rabbits ,Adrenergic alpha-Agonists - Abstract
Midodrine hydrochloride is a peripheral alpha(1)-adrenoreceptor agonist that induces venous and arterial vasoconstriction. Midodrine, after oral or intravenous administration, undergoes enzymatic hydrolysis and releases deglymidodrine, a pharmacologically active metabolite. Midodrine and deglymidodrine have a chiral carbon in the 2-position. To investigate the bioactivity of racemates and enantiomers of the drug and metabolite, three chromatographic chiral stationary phases, Chiralcel OD-H, Chiralcel OD-R, and alpha(1)-AGP, were evaluated for enantiomeric resolution. Good enantioseparation of midodrine racemate was obtained using the Chiralcel OD-H column. This stationary phase was then used to collect separately the midodrine enantiomers. By alkaline hydrolysis of rac-midodrine and each separated enantiomer, rac-deglymidodrine and its enantiomers were prepared. The control of the enantiomeric purity was carried out by alpha(1)-AGP stationary phase, while the hydrolysis of rac-midodrine and its enantiomers was controlled by capillary electrophoresis using trimethyl-beta-cyclodextrin as chiral selector. The pharmacological activity of the two racemates and the two enantiomeric pairs was tested in vitro on a strip of rabbit descending thoracic aorta. The tests continued that the activity of the drug and metabolite is due only to the (-)-enantiomer because neither of the (+)-enantiomers is active.
- Published
- 2004