Fate and disposition of bromocriptine in animals and man. I: Structure elucidation of the metabolites

Abstract

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.

Cyclosporin‐phenytoin interaction: re‐evaluation using metabolite data.

“…Before commencing any data analysis, the identity of one metabolite must be questioned, (Maurer et al, 1984). This metabolite is designated hereafter as metabolite X, although the identity of the metabolite is not crucial to the interpretation of the data.…”

High affinity of ergopeptides for cytochromes P450 3A

“…In some incubations, the formation of isobromocriptine and its hydroxylated metabolites was detected. These compounds derived from an epimerization at position 8 of the corresponding bromocriptine derivatives; they have been observed in the in vivo metabolism of bromocriptine (Maurer et al, 1982(Maurer et al, , 1983. The relative amounts of these isobromocriptine derivatives greatly depended on the time spent between the incubation and HPLC analysis.…”

“…As metabolism of bromocriptine in vivo in rats and humans, and in rat hepatocytes, has been found to lead to stereoisomers of 8'-hydroxybromocriptine and 8',9'-dihydroxybromocriptine (Maurer et al, 1982(Maurer et al, , 1983 as main oxidation metabolites, it is very likely that metabolites MI and M, are the stereoisomers of 8'-hydroxybromocriptine while M, and M, are stereoisomers of 8',9'-dihydroxybromocriptine. Fig.…”

“…In addition, this drug can correct abnormal secretions of growth hormone. Its metabolism has been studied in animals and man, in vivo and in cell cultures (Maurer et al, 1982(Maurer et al, , 1983. Primary oxidation occurs on the proline ring of the pseudopeptide moiety of the molecule and leads to 8'-hydroxy-bromocriptines.…”

Effects of bromocriptine on hepatic cytochrome P-450 monooxygenase system.

“…Indeed, it has been demonstrated that Br is extensively metabolized in the liver of both animals and man and that hydrolysis, isomer ism and oxidation accounted for most of its metabolism (2 were determined by the method of Lowry et al (5), using bovine serum albumin as the standard. Cytochrome P-450 levels in micro somes were determined by the method of Omura and Sato (6).…”