Chiral investigation of midodrine, a long-acting alpha-adrenergic stimulating agent.
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.
Quaglia
M G
MG
Dipartimento di Studi Farmaceutici, Università "La Sapienza", Rome, Italy. mariagiovanna.quaglia@uniroma1.it
Farina
A
A
Palmery
M
M
Desideri
N
N
Donati
E
E
Bossù
E
E
Strano
S
S
D000316:Adrenergic alpha-Agonists / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000473:pathology; D002244:Carbon / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D019075:Electrophoresis, Capillary; D006868:Hydrolysis; D008879:Midodrine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*; D008956:Models, Chemical; D011817:Rabbits; D013237:Stereoisomerism
D000316:Adrenergic alpha-Agonists; C118086:deglymidodrine; D008879:Midodrine; D002244:Carbon