Quercetin nanoparticles alter pharmacokinetics of bromocriptine, reflecting its enhanced inhibitory action on liver and intestinal CYP 3A enzymes in rats.

1. Quercetin is a dietary flavonoid has extremely low water solubility and found to possess CYP3A inhibitory activity. The purpose of the present study was to evaluate the effect of quercetin and quercetin nanoparticles (NQC) on the pharmacokinetics of bromocriptine (BRO) in rats. 2. NQC prepared by antisolvent precipitation method and characterized by SEM and dissolution test. The following methods were used in this study i.e. in vitro liver and intestinal CYP3A microsomal activity and in vitro non-everted sac method. To confirm these findings, an in vivo pharmacokinetic study was also performed. 3. The results indicate that quercetin significantly (p < 0.05) inhibited the CYP3A activity in liver and intestinal microsomes. In non-everted sac study, the intestinal transport and Papp of BRO were significantly increased in NQC and quercetin groups. Furthermore, in vivo study revealed that the increased levels of Cmax and AUC were comparatively high in NQC pretreated group than quercetin group. In addition, pretreatment with quercetin and NQC significantly (p < 0.05) decreased the mean CL/F and Vd/F of BRO. 4. NQC pretreatment might be result in higher plasma levels of quercetin that could inhibit the CYP3A enzyme and enhanced the bioavailability of BRO.

Simultaneous RP-HPLC-DAD quantification of bromocriptine, haloperidol and its diazepane structural analog in rat plasma with droperidol as internal standard for application to drug-interaction pharmacokinetics.

A simple and rapid RP-HPLC-DAD method was developed and validated for simultaneous determination of the dopamine antagonists haloperidol, its diazepane analog, and the dopamine agonist bromocriptine in rat plasma, to perform pharmacokinetic drug-interaction studies. Samples were prepared for analysis by acetonitrile (22.0 microg/mL) plasma protein precipitation with droperidol as an internal standard, followed by a double-step liquid-liquid extraction with hexane : chloroform (70:30) prior to C-18 separation. Isocratic elution was achieved using a 0.1% (v/v) trifluoroacetic acid in deionized water, methanol and acetonitrile (45/27.5/27.5, v/v/v). Triple-wavelength diode-array detection at the lambda(max) of 245 nm for haloperidol, 254 nm for the diazepane analog and droperidol, and 240 nm for bromocriptine was carried out. The LLOQ of DAL, HAL, and BCT were 45.0, 56.1, and 150 ng/mL, respectively. In rats, the estimated pharmacokinetic parameters (i.e., t(1/2), CL, and V(ss)) of HAL when administered with DAL and BCT were t(1/2) = 16.4 min, V(ss) = 0.541 L/kg for HAL, t(1/2) = 28.0 min, V(ss) = 2.00 L/kg for DAL, and t(1/2) = 24.0 min, V(ss) = 0.106 L/kg for BCT. The PK parameters for HAL differed significantly from those previously reported, which may be an indication of a drug-drug interaction.

Sensitive method for the quantitative determination of bromocriptine in human plasma by liquid chromatography-tandem mass spectrometry.

A sensitive LC-MS-MS assay for the quantitative determination of bromocriptine has been developed and validated and is described in this work. The assay involved the extraction of the analyte from 1 ml of human plasma using a solid phase extraction on Oasis MCX cartridges. Chromatography was performed on a Symmetry C18 (2.1 mm x 100 mm, 3.5 microm) column using a mobile phase consisting of 25:75:01 acetonitrile-water-formic acid with a flow rate of 250 microl/min. The linearity was within the concentration range of 2-500 pg/ml. The lower limit of quantification was 2 pg/ml. This method has been demonstrated to be an improvement over existing methods due to its greater sensitivity and specificity.

Inhibition of lactation by a long-acting bromocriptine.

A long-acting form of bromocriptine, a prolactin (PRL) secretion inhibitor, was administered to 122 postpartum women in single intramuscular injections of 20 (N = 24), 30 (N = 22), 40 (N = 46), and 50 mg (N = 30). In 91 women the substance was administered immediately after delivery to prevent galactopoiesis and in the remaining 31 women to inhibit established lactation. Effectiveness was estimated by the absence of breast engorgement and of milk secretion. Successful prevention or inhibition of lactation was highest among women receiving 50 mg bromocriptine (97%), and comparison between dosages revealed a close linear dose-response relationship (r = 0.98). Persistent and significant (P less than .001) PRL inhibition could be recorded for up to 22 days in successfully treated puerperas in comparison with 12 normally breast-feeding women who served as control subjects. No significant side effects or local reactions were recorded. Eleven of 46 postpartum women receiving 20 or 30 mg bromocriptine experienced onset of milk secretion or lactation rebound, and responded to oral administration of the drug. The presence of milk was associated with plasma PRL concentrations persistently above 25 ng/mL in all of them, whereas nine women in the same dosage range in whom lactation suppression was effective exhibited values below this limit. Dose-response data allow the establishment of a putative PRL threshold for induction of milk secretion of about 25 ng/mL. Maintenance of plasma PRL values below this limit prevents lactogenesis and inhibits lactopoiesis.

Increased circulating levels of bromocriptine after vaginal compared with oral administration.

OBJECTIVE: To compare the circulating levels of bromocriptine after oral and vaginal administration of the drug. DESIGN: Experimental PARTICIPANTS: Seven ovulatory female volunteers and one hyperprolactinemic patient. INTERVENTIONS: Ovulatory volunteers were randomized to receive either oral or vaginal bromocriptine (2.5 mg). In a second session, the subjects were crossed-over to bromocriptine by the alternate route. An additional hyperprolactinemic patient received vaginal bromocriptine only. MAIN OUTCOME MEASURE: Serum bromocriptine and prolactin (PRL) levels were measured hourly for 12 hours in the normal volunteers and for 10 hours in the hyperprolactinemic patient. RESULTS: Circulating bromocriptine levels were significantly higher after vaginal bromocriptine after the 7th hour (P less than 0.05). The reduction in serum PRL was significantly greater after oral administration between 2 and 6 hours. CONCLUSIONS: Vaginally administered bromocriptine may result in a reduction in the overall dose required, thereby improving compliance without compromising therapeutic efficacy.

Low dose bromocriptine: a study of acute effects in chronic mediated schizophrenics.

An acute low oral dose (2 mg) of bromocriptine was administered in a randomized double blind fashion to 11 chronic symptomatic mediated schizophrenic patients. There was an overall improvement for the group on the Brief Psychiatric Rating Scale (BPRS) following bromocriptine. Plasma homovanillic acid, 3-methoxy-4-hydroxyphenylglycol, and vanilloyl-mandelic acid concentrations were unchanged after bromocriptine. Bromocriptine concentrations in the plasma showed a large inter-individual variation. There was a significant inverse correlation between plasma bromocriptine concentration and total BPRS score at 60 minutes post-bromocriptine administration. These results suggest a need for further replication in a larger study population and a need for controlled studies with chronic administration of low dose bromocriptine in chronic medicated schizophrenic patients.

The influence of levodopa in the pharmacokinetics of bromocriptine in Parkinson's disease.

The administration of bromocriptine in addition to levodopa in Parkinson's disease produces beneficial results. Several hypotheses have explained the advantage of the combined treatment by a pharmacodynamic interaction in the striatum. However, no study has considered the possibility that levodopa modifies the kinetics of bromocriptine. In the present study performed with parkinsonian patients, we measured blood levels of bromocriptine (by radioimmunoassay) at 0, 30, 60, 90, 120, 180, and 240 min after the oral administration of bromocriptine alone and together with 250 mg levodopa plus 25 mg DCI. After loading of bromocriptine alone, we found mean peak levels at 60 min (1.42 ng/ml) and at 90 min (1.82 ng/ml). These values were reduced by levodopa (0.97 ng/ml at 60 min and 0.93 ng/ml at 90 min). Although we did not observe substantial clinical differences among the groups after the drug challenge (Webster scale), this study supports our previous findings and suggests that one of the advantages of a combined treatment may result from a modification of the plasma levels of bromocriptine by levodopa. A "smoothing" of the plasma bromocriptine curve possibly avoids sudden oscillations of the drug and enables a more "stable" penetrability of the medication into the central nervous system. Therefore long-term combined treatment is advised in preference to bromocriptine alone.

Sensitive and specific bromocriptine radioimmunoassay with iodine label: measurement of bromocriptine in human plasma.

Plasma bromocriptine assays must have high sensitivity because plasma concentrations are low, and high specificity because bromocriptine is extensively metabolised. This paper describes the simple preparation of a radioiodine-labelled derivative of dihydroergocriptine and its use in a radioimmunoassay employing an antiserum directed against the intact bromocriptine molecule. The method could measure plasma bromocriptine at concentrations of 0.05 nmol/L, had between-assay coefficients of variation of less than 10% and was more convenient than previous assays using tritium radiolabels.

[Hemodynamic and biological effects of bromocriptine in essential hypertension]. / Effets hémodynamiques et biologiques de la bromocriptine dans l'hypertension artérielle essentielle.

Central dopaminergic dysfunction has been suggested as the cause of essential hypertension. Agonist dopaminergic substances (AD) possess documented anti-hypertensive properties. We studied the cardiovascular effects of a single oral dose of 10 mg of Bromocriptine (Br) in untreated subjects with essential hypertension. A number of hemodynamic and biological parameters (direct blood pressure, pulmonary arterial and capillary pressures, cardiac index, heart rate, right ventricular and left ventricular work indices, systemic arterial and pulmonary vascular resistance, plasma renin activity, prolactin, and circulating Br levels) were measured before and after ingestion of the drug (at I, 1,5, 2, 3, 4, 5, 6, 8, 10 and 12 hours). Despite great individual variability, under the experimental conditions, Br displayed a strong anti-hypertensive action. The fall in blood pressure was early (Ist our) progressive, stabilising between the 3rd and 6th hour and prolonged (12 hour). This response was independent of the basal blood pressure with basal plasma renin activity (R = 0.64; p less than 0.05) but not with the prolactin level. The left ventricular work index underwent a similar change. Systemic arterial resistance fell, but this occurred after the fall in blood pressure. There was an independent and significant fall in pulmonary arterial pressure and pulmonary vascular resistance. The prolactin level fell very quickly and remained low throughout the 12 hours. There was an excellent correlation between the direct blood pressure and prolactin level (r = 0.97; p less than 0.01). Plasma renin activity rose after the third hour to reach a maximum at the 8th hour. There was a weak correlation between the blood pressure and plasma renin activity (r = 0.65, p less than 0.05). The serum Br level varied from patient to patient but reached a maximum at 1 hour, remaining stable until the 6th hour before decreasing. There was a correlation between the plasma renin activity and prolactin levels at each dosage (r = 0.66; p less than 0.005). The hemodynamic effects of Br are similar to those of central anti-hypertensive agents. The changes in plasma renin activity are comparable to those observed in central dopaminergic dysfunction. The excellent chronological correlation between the change in blood pressure and prolactin level is compatible with the hypothesis of this type of dysfunction in essential hypertension, if the inhibition of prolactin is accepted as a central dopaminergic effect of bromocriptine.

[Effects of therapy and pregnancy on hyperprolactemia caused by a pituitary adenoma. A clinical case]. / Effetti della terapia e della gravidanza nella iperprolattinemia da adenoma ipofisario. Caso clinico.

A woman who presented with amenorrhea and galactorrhea with a large prolactinoma (8.5 mm) which regressed on bromocriptine therapy is described. When treatment with bromocriptine was instituted (10 mg/daily) mean serum prolactin concentration fell from 490 ng/ml to 108 ng/ml. Despite a progressive reduction in size up to disappearance of the adenoma after the first 5 years of therapy, prolactin levels remained high. Bromocriptine treatment was stopped after 6 years, when pregnancy was diagnosed. Pregnancy proceeded without complications and lactation was initiated and maintained. After 8 months of breast-feeding, menstrual function resumed spontaneously and bromocriptine therapy was no longer required. Bromocriptine can cause not only a decrease in serum prolactin levels but also a regression in the size of prolactinomas in hyperprolactinemic women. No problems associated with pregnancy and/or breast-feeding were noted in these patients.

The effect of food and metoclopramide on the pharmacokinetics and side effects of bromocriptine.

The effect of food and metoclopramide on the pharmacokinetics of bromocriptine was investigated in 7 healthy subjects. Plasma concentrations of bromocriptine were measured by radioimmunoassay after a single oral dose of 7.5 mg bromocriptine. Maximal plasma concentrations of bromocriptine were slightly lower when the drug was given after breakfast. Bioavailability of the drug was not significantly reduced by food nor by metoclopramide pre-treatment. Side effects of bromocriptine were considerably reduced by metoclopramide pre-treatment (0.5 mg/kg); the decrease was about 83% as estimated from Table II.

Determination of bromocriptine in plasma: comparison of gas chromatography, mass fragmentography and liquid chromatography.

Gas chromatographic, mass fragmentographic and liquid chromatographic techniques for the determinations of bromocriptine (2-bromo-alpha-ergocriptine; Parlodel) in human plasma are described. These methods were found to be suitable for determining concentrations of bromocriptine down to 0.5, 1.0 and 10.0 microgram/l, respectively. Accuracy, specificity and analytical capacity were satisfactory for all three methods. Gas chromatography was compared with liquid chromatography, and the two methods were demonstrated to give identical results in patients treated with bromocriptine for Parkinson's disease. Gas chromatography was also compared with mass fragmentography, and the results from these two assays were also in agreement.

Pharmacokinetics of bromocriptine during continuous oral treatment of Parkinson's disease.

The plasma kinetics of bromocriptine (BCT), a long-acting dopamine agonist, was studied in twelve patients with Parkinson's disease, using a newly developed gas chromatographic method of analysis. Each patient received BCT for at least three weeks in a constant but different dose regimen. Concomitant treatment with 1-DOPA was not allowed. During a 6-day hospitalization period, a blood sample was taken immediately before the afternoon dose at 14.00 h (Cmin) to determine the steady-state level. On the 6th day blood samples were collected every hour during two 8 h dose intervals. The results showed a significant correlation between the mean values of the AUC and the Cmin. First order elimination kinetics appeared to be followed by BCT, at least for the plasma concentrations commonly found. Considerable inter-individual variation was demonstrated both for the dose/plasma concentration ratio and for calculated plasma clearances. No serious side-effects were observed during the investigation.

Triple stage quadrupole mass spectrometric determination of bromocriptine in human plasma with negative ion chemical ionization.

A new MS/MS assay for the quantitative determination of bromocriptine in body fluids is presented. The selective reagent gas in combination with the registration of selected, characteristic negative ions (SIM) after collision activated decomposition (CAD) in a Triple-Stage-Quaddrupole-mass spectrometer, provides an exceptional selective and sensitive assay in the low pg/ml range. The lower limit of detection was about 1 pg/ml (at optimal measuring conditions) and the calibration curve was linear in the range of 10-200 pg/ml. The coefficient of variation for the imprecision and inaccuracy data was typically below 10%; the recovery from plasma always exceeded 75%. The sample introduction to the mass spectrometer was done by a direct exposure probe (DEP). Thus, the method is well suited for the reliable, rapid processing of large sample numbers generated e.g. from clinical studies evaluating the pharmacokinetics and/or bioavailability/bioequivalence of different formulations or from drug monitoring/clinical response programs. The assay has been successfully approved in several clinical studies evaluating different bromocriptine preparations.

Efficacy of a new long-acting injectable form of bromocriptine in hyperprolactinaemic patients.

OBJECTIVE: The objective of this study was to assess the relationship of different doses of a long-acting bromocriptine preparation (Parlodel LAR) to the degree and duration of PRL suppression. We also measured circulating bromocriptine levels and altered tolerability of the drug. DESIGN: A double-blind randomized study of three different doses 25, 50 and 100 mg of Parlodel LAR. PATIENTS: Twenty-one female patients (seven patients/dose) with both tumoral and non-tumoral hyperprolactinaemia. MEASUREMENTS: After a single injection of Parlodel LAR 25, 50 or 100 mg, serum PRL and plasma bromocriptine levels were assessed during a follow-up of 60 days together with changes in clinical symptoms and signs of hyperprolactinaemia. RESULTS: Serum PRL levels normalized in 19 of 21 patients. The suppression of PRL secretion lasted 28 days in four of seven patients treated with either 25 or 50 mg Parlodel LAR and in five of seven patients who received Parlodel LAR 100 mg. In five of seven patients treated with the 100 mg dose, serum PRL levels were still within the normal range on day 60. Plasma bromocriptine levels remained therapeutically active for 28 days in all three groups. On day 60 they were within the therapeutic range only in the 100 mg group. Clinical data show a rapid disappearance of symptoms and signs of hyperprolactinaemia. Adverse events were mostly mild and transient. CONCLUSIONS: These data support the excellent efficacy and good tolerability of Parlodel LAR in patients with hyperprolactinaemia.

Bromocriptine in Parkinsonism.

A review of the effects of using bromocriptine in Parkinson's disease showed that it rarely helps patients not primarily improved by levodopa. Patients who show late failure with levadopa and whose response to treatment is declining are helped by combining the two drugs. High cost and severe psychosis are the main disadvantages of bromocriptine, and, although it is not recommended for patients who are doing well on levodopa, it is the best available drug for hospital use in patients who show late failure with levodopa.

The rapid diagnosis of sensitivity or resistance to dopamine agonists with depot bromocriptine.

Some patients with hyperprolactinaemia are unable to tolerate even low doses of oral bromocriptine. In such cases, it is difficult to predict whether serum prolactin might be normalized if higher doses could be tolerated, or whether true resistance to bromocriptine is present. We have investigated 8 such patients who were subjected to a dopamine infusion (4 micrograms/kg per min for 4 h), followed by an injection of 50 mg of depot bromocriptine on a separate occasion. Serum prolactin was normalized in 4 patients during dopamine, and in 6 patients 12-48 h following depot bromocriptine. The 2 patients who failed to respond to depot bromocriptine also failed to respond to high oral doses of bromocriptine, while the remaining 6 patients were successfully transferred to oral bromocriptine without adverse reactions after the depot preparation was administered, and with a normalization of serum prolactin. It is concluded that depot bromocriptine may represent a better predictor of true unresponsiveness to dopamine agonist therapy than a dopamine infusion, and may also allow for initiation onto oral therapy of previously intolerant patients.

Effect of bromocriptine treatment on circulating somatomedins in tall adolescents.

Somatomedin and bromocriptine levels were measured before and after 3 months of bromocriptine treatment (5 mg/day) in the sera of 16 tall adolescents with excessive adult height prediction. Somatomedins were measured by RIA for somatomedin C and IgFII and by measuring thymidine incorporation into human lectin-activated lymphocytes. Mean +/- SEM levels of bromocriptine after three months of treatment were 0.61 +/- 0.08 ng/ml. No changes in radioimmunoassayable somatomedin C were observed after bromocriptine intake respectively 1.34 +/- 0.17 U/ml before and 1.4 +/- 0.01 U/ml during treatment. On the opposite a significant decrease of thymidine activity (p less than 0.002) from 1.45 +/- 0.17 U/ml to 1.12 +/- 0.19 U/ml was observed. No changes of IgFII levels were observed in the sera of the 8 patients where they were measured. In order to test a possible direct effect of bromocriptine on peripheral tissues bromocriptine mesylate was added in somatomedin bioassays. Inhibitory effect of bromocriptine in vitro is seen at higher levels (1 microM) compared to the circulating one (1 nM). This study demonstrates that the major effect of bromocriptine which is the acceleration of bone maturation is not related to changes in somatomedin C.