Analyte Names and Structures:
Bromocriptine

Synonyms:
For Bromocriptine - CB154
For Bromocriptine Mesylate - Parlodel®, Parlodel Snap Tabs®

bromocriptine.jpg
Relevant Physicochemical Data:

Bromocriptine:
Chemical Names: (5′α)-2-bromo-12′-hydroxy-2′-(1-methylethyl)-5′-(2-methylpropyl)ergotaman-3′,6′,18-trione;
2-bromo-α-ergocriptine; 2-bromo-α-ergokryptin
CAS No.: 25614-03-3
Molecular formula: C32H40BrN5O5
Molecular weight: 654.59
Crystalline solid
No information on solubility
Melting point: 215 - 218 °C, with decomposition
Infra-red spectrum: principal peaks at wavenumbers 1170, 1633, 1217, 1660, 1715, 1045 cm-1
Mass spectrum: principal ions at m/z = 70, 43, 154, 71, 41, 209, 86, 195

Bromocriptine Mesylate (Bromocriptine Methanesulfonate):
Chemical Names: (5′α)-2-bromo-12′-hydroxy-2′-(1-methylethyl)-5′-(2-methylpropyl)ergotaman-3′,6′,
18-trione methanesulfonate; 2-bromo-α-ergocriptine methanesulfonate; 2-bromo-α-ergokryptin methanesulfonate
CAS No.: 22260-51-1
Molecular formula: C32H40BrN5O5 • CH3SO3H
Molecular weight: 750.70
Yellowish-white crystalline powder
Very soluble at 25 °C in methanol (910 mg/mL); sparingly soluble in ethanol (23 mg/mL); very slightly soluble in water
(0.8 mg/mL) and chloroform (0.45 mg/mL); essentially insoluble in benzene and hexane (<0.1 mg/mL)
Melting point: 192 - 196 °C, with decomposition
pKa = 4.90

General Relevancy:
Bromocriptine is an ergot derivative that is chemically related to compounds such as d-lysergic acid diethylamide (LSD), ergotamine, ergonovine and methylergonovine. Pharmacologically, the drug acts as a partial dopamine receptor agonist and antagonist in various parts of the brain. Although the compound mimics many of the actions of dopamine, it is not metabolized as readily as dopamine. Since dopamine is believed to be involved in regulating (i.e., inhibiting) the secretion of prolactin, bromocriptine acts as an inhibitor of prolactin secretion from the anterior pituitary gland.

Bromocriptine is indicated for use in the following conditions: (1) Parkinson’s Disease, (2) hyperprolactinemia-associated dysfunctions, and (3) acromegaly. The drug has also used (unlabeled uses) for treating cocaine addiction, the neuroleptic malignant syndrome, and cyclical mastalgia. The chemical basis (or hypothesis) behind all of these conditions is a reduction in the secretion of the neurotransmitter dopamine in specific parts of the brain. Since bromocriptine acts as to stimulate dopamine receptors, it acts as a substitute for dopamine.

Parkinson’s Disease. This drug is used as an adjunct to levodopa for the treatment of idiopathic or post-encephalitic Parkinson’s disease. Therapy with bromocriptine may provide additional benefits in those patients who are currently maintained on optimal dosages of levodopa, those who are beginning to develop tolerance to levodopa, and those who are experiencing levodopa “end of dose failure.” Bromocriptine may allow for a reduction in the maintenance dose of levodopa and therefore may reduce the occurrence or severity of adverse reactions associated with long-term levodopa therapy. After initial therapy with low doses (e.g., 1.25 mg twice daily) to build up tolerance to potential adverse effects, oral doses of the drug for Parkinson’s disease range between 10 and 40 mg per day.

Hyperprolactinemia-associated Dysfunctions. Bromocriptine is indicated for use in both males and females for the treatment of dysfunctions associated with (a) hyperprolactinemia including amenorrhea with or without galactorrhea, (b) hypogonadism, and (c) infertility. The drug is indicated for use in patients with prolactin-secreting adenomas that may be the underlying pathology of the clinical presentations. The usual oral dosage range for the treatment of hyperprolactinemic conditions is 2.5 to 15 mg per day.

Acromegaly. Acromegaly is a disorder marked by progressive enlargement of peripheral body parts, especially the head, face, hands, and feet. This condition is caused by the excessive secretion of somatotropin (growth hormone). Bromocriptine, alone or as adjunct therapy with pituitary irradiation or surgery, reduces serum growth hormone and is useful in treating this condition. After initial therapy with low doses (e.g., 1.25 to 2.5 mg daily) the dosage is gradually increased as tolerated by the patient. The usual optimal therapeutic dosage range for the treatment of acromegaly is 20 to 30 mg per day.

Bromocriptine mesylate (Parlodel®) is available as tablets of 2.5 mg and capsules of 5 mg.

Pharmacokinetics(TDM):
Bromocriptine is rapidly absorbed after oral administration with the drug appearing in the plasma in 10 minutes in one study; maximum plasma concentrations were reportedly attained in 1 to 1.5 hours. However, the oral absorption from the gastrointestinal tract is only approximately 28%. In addition, the drug undergoes first-pass metabolism in the liver, such that the oral bioavailability is only approximately 6%.

Bromocriptine is about 90 to 96% bound to serum albumen. It has been observed that bromocriptine and its metabolites do not distribute appreciably in erythrocytes. The volume of distribution is approximately 3 L/kg. It is not known whether the drug distributes to breast milk or distributes to the fetus in pregnant women.

The drug is metabolized in liver by hydrolysis and isomerization to 2-bromolysergic acid and 2-bromoisolysergic acid, and by hydrolylation, further oxidation and conjugation to produce a large number of metabolites. Metabolism of bromocriptine is almost complete prior to elimination and none of the metabolites are believed to have pharmacological activity.
The bile is the major route of excretion. About 70 to 85% of the drug is elimination in the feces through the bile within 5 days of a single oral dose. Only 2.5 to 7% of a dose is excreted in the urine as metabolites (a small fraction as unchanged drug).

Bromocriptine apparently follows a two-compartment pharmacokinetic model. The elimination half-life the distribution α-phase is estimated to be between 3 and 4.5 hours; the elimination half-life the terminal β-phase is estimated to be approximately 40 to 45 hours.

Diagnostic Significance (Endocrinology):

Proper Specimen Types:
Serum or plasma – preferred
Whole blood – alternate

Analyte(s) to be Determined:
Bromocriptine


Methods of Analysis:
1.
Liquid chromatography/Tandem Mass Spectrometry – preferred to get to pg/mL (i.e., sub-ng/mL) concentrations (see method described by Salvador et al., 2005).

In this paper, the internal standard, α-ergocryptine, was used (see structure below); this compound is available from Sigma-Aldrich, St. Louis, MO. The lower limit of quantification (LLOQ) was reported to be 2 pg/mL (0.002 ng/mL) and the linear range of the LC/MS/MS analysis was 2 to 500 pg/mL (0.002 to 0.5 ng/mL).

bromocriptine2.jpg


2.
Gas Chromatography and Gas Chromatography/Mass Spectrometry have been used to quantify with the following limits of detection: GC = 0.5 ng/mL and GC/MS = 1 ng/mL (see Larsen et al., 1979).
Measurable Range (Upper/Lower Detection Limits)::

Critical Concentrations:
As noted below, plasma concentrations reported were all derived by RIA methodology.

There appears to be a difference between blood and serum/plasma concentrations (as noted above, bromocriptine and its metabolites do not distribute appreciably into erythrocytes). Using radiolabeled drug, blood concentrations of the parent drug and its metabolites following an oral dose of 2.5 mg of bromocriptine were reported to be approximately 2 to 3 ng/mL while plasma concentrations following this dose were reported to be about 4 to 6 ng/mL [measured by RIA] (see Facts and Comparisons, p. 365; AHFS, p. 3677).

It is noted that there are large interindividual variations in plasma concentrations of bromocriptine with fixed oral dosages. Furthermore, plasma concentrations required for antiparkinsonian and prolactin-lowering effects are not known (see Friis et al., 1979).

In one study, 13 patients with acromegaly were given bromocriptine (5 mg orally, twice daily) for several days. After 7 days of treatment, the mean peak plasma concentration (tmax) occurred at 1.2 ± 0.4 hours, the mean maximum plasma concentration (Cmax) was 628 ± 375 pg/mL (0.628 ± 0.375 ng/mL), and the mean minimum plasma concentration (Cmin) was 75 ± 39 pg/mL (0.075 ± 0.039 ng/mL) [measured by RIA] (see Flogstad et al., 1994).

Following daily oral administration of 60 to 150 mg in divided doses to 4 subjects with Parkinson’s disease, trough steady-state concentrations of 9 to 54 ng/mL: (mean = 30 ng/mL) and saliva concentrations of 0.1 to 0.4 ng/mL were reported [measured by RIA] (see Friis et al., 1980).

Peak plasma concentrations after a single oral dose of bromocriptine were reported as:

25 mg to 9 subjects = 1 to 4 ng/mL in about 90 minutes
50 mg to 7 subjects = 3 to 20 ng/mL (mean = 10 ng/mL) in about 90 minutes
100 mg to 5 subjects = 6 to 25 ng/mL (mean = 10 ng/mL) in about 120 minutes

(see Price et al., 1978).

Potential Interfering Compounds:

Stability Data:
Data from one paper (see Salvador et al., 2005) showed that bromocriptine is stable in human plasma:

For at least 4 hours at room temperature,
Through at least 3 freeze-thaw cycles, and
For at least 10 weeks when frozen at –25 °C.

No other stability data was found.

Interpretative Comment(s):
No therapeutic reference ranges have been established due to the variability in dosage regimens, large interindividual variations in patients with fixed dosages, and differences in methodology.

References:

Flogstad, A.K., J. Halse, P. Grass, E. Abisch, O. Djoseland, K. Kutz, E. Bodd and J. Jervell (1994): “A comparison of octreotide, bromocriptine, or a combination of both drugs in acromegaly,” J. Clin. Endocrinol. Metab. 79: 461-465.

Friis, M.L., U. Gron, N.E. Larsen, H. Pakkenberg and E.F. Hvidberg (1979): “Pharmacokinetics of bromocriptine during continuous oral treatment of Parkinson’s disease,” Eur. J. Clin. Pharmacol. 15: 275-280.

Friis, M.L., T. Johnson, N.E. Larsen, E.F. Hvidberg and H. Pakkenberg (1980): “Bromocriptine concentration in saliva and plasma after long-term treatment of patients with Parkinson’s disease,” Eur. J. Clin. Pharmacol. 18: 171-174.

Larsen, N.E., R. Ohman, M. Larsson and E.F. Hvidberg (1979): “Determination of bromocriptine in plasma: comparison of gas chromatography, mass fragmentography and liquid chromatography,” J. Chromatogr. 174: 341-349.

Lieberman, A.N., and M. Goldstein (1985): “Bromocriptine in Parkinson disease,” Pharmacological Reviews 37: 217-227.

Price, P, A. Debono, J.D. Parkes, C.D. Marsden and J. Rosenthaler (1978): “Plasma bromocriptine levels, clinical and growth horone responses in Parkinsonism,” Br. J. Clin. Pharmacol. 6: 303-309.

Ramey, J.M. Z. Oberman, M. Scharf, A. Isakov, M. Bar and E. Graff (1989): “The influence of levodopa in the pharmacokinetics of bromocriptine in Parkinson’s disease,” Clin. Neuropharmacol. 12: 440-447.

Salvador, A., D. Dubreuil, J. Denouel and L. Millerioux (2005): “Sensitive method for the quantitative determination of bromocriptine in human plasma by liquid chromatography-tandem mass spectrometry,” J. Chromatogr. B 820: 237-242.

Clarke’s Analysis of Drugs and Poisons, 3rd Edition (2004), Moffat, A.C., M.D. Osselton and B. Widdop (eds.), Pharmaceutical Press, London, pp. 711-712.

The Merck Index, 14th Edition (2006), O’Neil, M.J. (ed.), Merck & Co., Whitehouse Station, p. 1417.
Drug Facts and Comparisons (2007), Facts and Comparisons, Wolters Kluwer Health, St. Louis, pp. 365-366, 1087 (revised January 2000).

AFHS Drug Information (2007), McEvoy G.K. (ed), American Society of Health-System Pharmacists, Bethesda, pp. 3674-3678.