Plasma bromocriptine levels, clinical and growth hormone responses in Parkinsonism.

Price, Paul A.; Debono, A G; Parkes, J. D.; Marsden, C. D.; Rosenthaler, J.

doi:10.1111/j.1365-2125.1978.tb00856.x

Cited by 25 publications

(15 citation statements)

References 11 publications

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“…The more sensitive RIA technique has a detection limit of 0.1 to 0.15 ng/ml plasma (14,15) and has been found to be quite specific for the parent drug. The pharmacokinetic and bioavailability studies were made using an improved version of this procedure applicable to doses as low as 2.5 mg (8,14,16,17,18).…”

Section: Discussionmentioning

confidence: 99%

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

Maurer¹,

Schreier²,

Delaborde³

et al. 1983

European Journal of Drug Metabolism and Pharmacokinetics

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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, metabolites 6 and 1. 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 the in 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.

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Section: Discussionmentioning

confidence: 99%

“…The pharmacokinetic and bioavailability studies were made using an improved version of this procedure applicable to doses as low as 2.5 mg (8,14,16,17,18).…”

Section: Discussionmentioning

confidence: 99%

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

Maurer¹,

Schreier²,

Delaborde³

et al. 1983

European Journal of Drug Metabolism and Pharmacokinetics

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“…The absence of DILI may be due to extensive metabolism of bromocriptin, essentially by the cytochrome CYP3A subfamily 40,41 , which most likely leads to low intracellular concentration of bromocriptine in hepatocytes. In addition, unbound plasma concentrations of bromocriptin are about 60 times lower (15 nM, 42 ) than the IC 50 of bromocriptin in the vesicle assay (1.2 µM).…”

Section: Discussionmentioning

confidence: 99%

Flagging Drugs That Inhibit the Bile Salt Export Pump

et al. 2015

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The bile salt export pump (BSEP) is an ABC-transporter expressed at the canalicular membrane of hepatocytes. Its physiological role is to expel bile salts into the canaliculi from where they drain into the bile duct. Inhibition of this transporter may lead to intrahepatic cholestasis. Predictive computational models of BSEP inhibition may allow for fast identification of potentially harmful compounds in large databases. This article presents a predictive in silico model based on physicochemical descriptors that is able to flag compounds as potential BSEP inhibitors. This model was built using a training set of 670 compounds with available BSEP inhibition potencies. It successfully predicted BSEP inhibition for two independent test sets and was in a further step used for a virtual screening experiment. After in vitro testing of selected candidates, a marketed drug, bromocriptin, was identified for the first time as BSEP inhibitor. This demonstrates the usefulness of the model to identify new BSEP inhibitors and therefore potential cholestasis perpetrators. Just Accepted "Just Accepted" manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides "Just Accepted" as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. "Just Accepted" manuscripts appear in full in PDF format accompanied by an HTML abstract. "Just Accepted" manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). "Just Accepted" is an optional service offered to authors. Therefore, the "Just Accepted" Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the "Just Accepted" Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these "Just Accepted" manuscripts. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2 Table of 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 3 1 Flagging drugs that inhibit the bile salt export pump AbstractThe bile salt export pump (BSEP) is an ABC-transporter expressed at the canalicular membrane of hepa...

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“…Certainly the a-adrenoceptor blocking properties of bromocriptine may contribute to the postural nature of the fall in blood pressure in some patients; the role of the adrenal glands is less clear. However, as in the rat, there is some evidence that in man, bromocriptine-induced hypotension is not mediated by stimulation of dopamine receptors since the response persists after metoclopramide (Price et al, 1978) and was evident after domperidone, a peripherally-acting dopamine antagonist (Agid, Bonnet, Pollack, Signoret & Lhermitte, 1979 …”

Section: Discussionmentioning

confidence: 99%

“…Postural hypotension is one side effect of the clinical use of the dopamine agonist, bromocriptine, in the treatment of parkinsonism, acromegaly and infertility (O'Mullane, Davis, Hipkin & Walker, 1976; Greenacre, Teychenn, Petrie, Calne, Leigh & Reid, 1976;Brosens, 1977;Linch, Shaw, Muhlemann & Ross, 1978;Price, Debono, Parkes, Marsden & Rosenthaler, 1978). In the treatment of hypertension, bromocriptine has been used successfully either alone (Stumpe, Kollock, Higuchi, Kruck & Vetter, 1977) or in combination with other antihypertensive drugs (Kaye, Shaw & Ross, 1976;Lewis, Henderson & Fisher, 1976).…”

Section: Introductionmentioning

confidence: 99%

Involvement of the Adrenal Glands in the Hypotensive Response to Bromocriptine in Spontaneously Hypertensive Rats

Hamilton

1981

British J Pharmacology

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1 The dopamine agonist, bromocriptine, produced a hypotensive response following oral administration to conscious normotensive and spontaneously hypertensive (SH-) rats. 2 In SH-rats the dose-related falls in blood pressure to bromocriptine, 3 to 30 mg/kg orally or intraperitoneally, were biphasic, an initial fall at 1 h being followed by some recovery at 2 h and a subsequent fall in blood pressure at 4 and 6 h.3 The dopamine antagonists, metoclopramide, sulpiride, haloperidol and pimozide, had little or no effect on the hypotensive response to bromocriptine, 10 mg/kg orally, in SH-rats. 4 Pretreatment with a-methyl-p-tyrosine augmented the hypotensive response to bromocriptine, 10 mg/kg orally, in SH-rats.5 In adrenal demedullated SH-rats, the hypotensive response to bromocriptine, 3 to 30 mg/kg orally, was abolished.6 In SH-rats the hypotensive response to bromocriptine, 10 mg/kg orally, was prevented by the ,3-adrenoceptor blocking drugs, propranolol and oxprenolol, but was unaffected by (+)-propranolol and by the cardio-selective ,8-adrenoceptor blocking drug, atenolol. 7 In SH-rats pretreated with bromocriptine, 10 mg/kg orally, and then anaesthetized, the pressor responses to low doses of intravenous adrenaline were reversed to depressor, indicating that bromocriptine possesses a-adrenoceptor blocking activity.8 The results suggest that the hypotensive response to bromocriptine in conscious SH-rats is mediated by adrenaline released from the adrenal medullae which, in the presence of a-adrenoceptor blockade, stimulates vascular,f-adrenoceptors producing vasodilatation.

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Plasma bromocriptine levels, clinical and growth hormone responses in Parkinsonism.

Cited by 25 publications

References 11 publications

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

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

Flagging Drugs That Inhibit the Bile Salt Export Pump

Involvement of the Adrenal Glands in the Hypotensive Response to Bromocriptine in Spontaneously Hypertensive Rats

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