Fate and disposition of bromocriptine in animals and man. I: structure elucidation of the metabolites.
A total of 16 metabolites of bromocriptine could be isolated from rat bile and incubates of rat liver cell preparations using [6-methyl-14C]bromocriptine as substrate. Separation and purification was achieved by reversed-phase liquid chromatography and preparative thin-layer chromatography in conjunction with radioactivity monitoring. Structure elucidation was based on spectroscopic data (UV, IR, NMR, EI- and FD-MS) and the results of amino acid analysis after acid hydrolysis. Based on the identified metabolites four principal transformation process could be described: -Hydrolytic cleavage of the amide bridge leading to the formation of 2-bromolysergic acid amide (3) and 2-bromolysergic acid (7). -epimerization at position 8 of the bromolysergic acid moiety to the iso-derivatives (isobromocriptine, 2-bromo-isolysergic acid (6), its amide (1), etc.) -regiospecific oxidation at position 8' in the proline fragment generating stereoisomeric 8'-hydroxy-bromocriptines (21-24) -further oxidation of the 8'-hydroxylated derivatives by either the introduction of a second hydroxy group at position 9' to give dihydroxylated derivatives (detected as conjugates with glucuronic acid: metabolites 29, 30 and 31), or the opening of the proline ring under formation of the metabolites 4 and 5 containing glutamic acid instead of proline (7', 8'-seco- 8'-carboxy-bromocriptines). It is suggested that the primary and principal metabolic attack occurs at the proline fragment of the drug. In contrast to the biotransformation of ergoline compounds, none of the bromocriptine metabolites detected showed oxidative transformations in the lysergic acid half of the molecule.
D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D001971:Bromocriptine / Q000378:metabolism*; D055598:Chemical Phenomena; D002621:Chemistry; D002627:Chemistry, Physical; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008968:Molecular Conformation; D051381:Rats; D013045:Species Specificity; D014018:Tissue Distribution
D001971:Bromocriptine