, Volume 8, Issue 1, pp 51-62

Fate and disposition of bromocriptine in animals and man. II: Absorption, elimination and metabolism

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Summary

The disposition and biotransformation of bromocriptine were investigated in mouse, rat, dog, rhesus monkey and man following administration of the drug substance labelled with either tritium or carbon-14.

The enteral absorption of bromocriptine was incomplete and amounted to 30–40% of the dose as estimated directly from the sum of biliary and urinary excretion of radioactive compounds in bile duct cannulated rats and monkeys. The main route of elimination was the bile (80–93% of the absorbed dose). Only 1 to 6% of the radioactive dose was recovered in urine of intact animals and man.

Extensive biotransformation of bromocriptine is reflected by very complex metabolite profiles in all tested body fluids and by the almost complete absence of parent drug in urine and bile. Of the numerous drug-derived radioactive components seventeen could be identified. In animals the major urinary metabolites were 2-bromo-lysergic acid (7), its amide (3), and the respective isomers at position 8, metabolites6 and1. Bromolysergic acid (7) and bromoisolysergic acid (6) accounted for half of the radioactivity in human urine. In rat and monkey bile up to 40% of the radioactivity was associated with metabolites derived from the oxidation (hydroxylation, ring-opening) of the proline fragment (4, 5, 21–24, 29–31). The hydroxylated compounds were present in the form of conjugates with glucuronic acid. These were subsequently deconjugated in the intestine and recovered in the faeces as the free forms.

The presence of the parent drug as a major component in rat plasma following intravenous administration and its absence after oral administration indicated that the elimination of bromocriptine proceeded almost entirely by metabolism in the liver.In vitro studies with isolated rat hepatocytes and 10.000 g supernatant of human liver confirmed thein vivo findings.

Based on the structures of the identified metabolites it could be concluded that the biotransformation of bromocriptine in man occurred through the same principal pathways as in all investigated animal species.