Bromocriptine - How It Works

CLINICAL PHARMACOLOGY Bromocriptine mesylate is a dopamine receptor agonist, which activates post-synaptic dopamine receptors.

The dopaminergic neurons in the tuberoinfundibular process modulate the secretion of prolactin from the anterior pituitary by secreting a prolactin inhibitory factor (thought to be dopamine); in the corpus striatum the dopaminergic neurons are involved in the control of motor function.

Clinically, bromocriptine mesylate significantly reduces plasma levels of prolactin in patients with physiologically elevated prolactin as well as in patients with hyperprolactinemia.

The inhibition of physiological lactation as well as galactorrhea in pathological hyperprolactinemic states is obtained at dose levels that do not affect secretion of other tropic hormones from the anterior pituitary.

Experiments have demonstrated that bromocriptine induces long-lasting stereotyped behavior in rodents and turning behavior in rats having unilateral lesions in the substantia nigra.

These actions, characteristic of those produced by dopamine, are inhibited by dopamine antagonists and suggest a direct action of bromocriptine on striatal dopamine receptors.

Bromocriptine mesylate is a nonhormonal, nonestrogenic agent that inhibits the secretion of prolactin in humans, with little or no effect on other pituitary hormones, except in patients with acromegaly, where it lowers elevated blood levels of growth hormone in the majority of patients.

Bromocriptine mesylate produces its therapeutic effect in the treatment of Parkinson’s disease, a clinical condition characterized by a progressive deficiency in dopamine synthesis in the substantia nigra, by directly stimulating the dopamine receptors in the corpus striatum.

In contrast, levodopa exerts its therapeutic effect only after conversion to dopamine by the neurons of the substantia nigra, which are known to be numerically diminished in this patient population.

Pharmacokinetics Absorption Following single dose administration of bromocriptine mesylate tablets, 2 x 2.5 mg to 5 healthy volunteers under fasted conditions, the mean peak plasma levels of bromocriptine, time to reach peak plasma concentrations and elimination half-life were 465 pg/mL ± 226, 2.5 hrs ± 2 and 4.85 hr, respectively.

1 Linear relationship was found between single doses of bromocriptine mesylate and C max and AUC in the dose range of 1 to 7.5 mg.

2 The pharmacokinetics of bromocriptine metabolites have not been reported.

Food did not significantly affect the systemic exposure of bromocriptine following administration of bromocriptine mesylate tablets, 2.5 mg.

3 It is recommended that bromocriptine mesylate be taken with food because of the high percentage of subjects who vomit upon receiving bromocriptine under fasting conditions.

Following bromocriptine mesylate 5 mg administered twice daily for 14 days, the bromocriptine C max and AUC at steady-state were 628 ± 375 pg/mL and 2377 ± 1186 pg*hr/mL, respectively.

4 Distribution In vitro experiments showed that bromocriptine was 90% - 96% bound to serum albumin.

Metabolism Bromocriptine undergoes extensive first-pass biotransformation, reflected by complex metabolite profiles and by almost complete absence of parent drug in urine and feces.

In vitro studies using human liver microsomes showed that bromocriptine has a high affinity for CYP3A and hydroxylations at the proline ring of the cyclopeptide moiety constituted a main metabolic pathway.

5 Inhibitors and/or potent substrates for CYP3A4 might therefore inhibit the clearance of bromocriptine and lead to increased levels. (see PRECAUTIONS, drug interactions section) .

The participation of other major CYP enzymes such as 2D6, 2C8, and 2C19 on the metabolism of bromocriptine has not been evaluated.