Pharmacokinetics and pharmacodynamics of pergolide mesylate after oral administration in horses with pituitary pars intermedia dysfunction.

Published information on the pharmacokinetic and pharmacodynamic properties of pergolide is limited. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of oral pergolide in horses with pituitary pars intermedia dysfunction (PPID). The study design was a nonrandomized clinical trial. Six horses with PPID diagnosed by thyrotropin-releasing hormone (TRH) stimulation tests received pergolide at 4 µg/kg for 18 d. Plasma samples for determination of pergolide and ACTH concentration were collected 0.5 h before and 2 and 12 h after each administration of pergolide. Maximum plasma concentrations after the first oral dose of pergolide (0.104-0.684 ng/mL; median 0.261 ng/mL; interquartile range [IQR] 0.184-0.416 ng/mL) were not significantly different to the maximum steady-state concentration at day 18 (0.197-0.628 ng/mL; median 0.274; IQR 0.232-0.458 ng/mL). Chronic administration was not associated with drug accumulation (R = 1.09) and pergolide concentration reached steady state within 3 d. Throughout, concentrations of pergolide fluctuated considerably, with median plasma peak concentrations more than four times higher than median trough concentrations. Plasma ACTH concentration reduced significantly within 12 h of administration with further reductions occurring up to 10 d after the initiation of treatment. Although there were parallel fluctuations in the concentrations of pergolide and ACTH, timing of ACTH measurement in relation to the administration of pergolide did not have a significant effect. Alterations in the response to TRH were identified at 8 d with no further change being identified at 18 d. A small number of horses were studied. Oral pergolide results in significant suppression of pars intermedia activity within hours. Pergolide and ACTH concentrations fluctuated in tandem although correlation was poor. Fluctuations in pergolide concentration were consistent with a terminal elimination half-life of less than 12 h. To reduce the level of fluctuation of ACTH, twice-daily dosing of pergolide may be more appropriate.

Pharmacokinetics of pergolide after intravenous administration to horses.

OBJECTIVE: To determine the pharmacokinetics of pergolide after IV administration to horses. ANIMALS: 8 healthy adult horses. PROCEDURES: Pergolide mesylate was administered IV at a dose of 20 µg/kg (equivalent to 15.2 µg of pergolide/kg) to each horse, and blood samples were collected over 48 hours. Pergolide concentrations in plasma were determined by means of high-performance liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were determined on the basis of noncompartmental methods. RESULTS: After IV administration of pergolide, mean ± SD clearance, elimination half-life, and initial volume of distribution were 959 ± 492 mL/h/kg, 5.64 ± 2.36 hours, and 0.79 ± 0.32 L/kg, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: With an elimination half-life of approximately 6 hours, twice-daily dosing may be more appropriate than once-daily dosing to reduce peak-trough fluctuation in pergolide concentrations. Further pharmacodynamic and pharmacokinetic studies of pergolide and its metabolites will be necessary to determine plasma concentrations that correlate with clinical effectiveness to determine the therapeutic range for the treatment of pituitary pars intermedia dysfunction.

Determination of pergolide in horse plasma by UPLC-MS/MS for pharmacokinetic applications.

Pergolide, an ergot-derived dopamine D2 receptor agonist, is used extensively as an orally administered treatment for pituitary pars intermedia dysfunction (PPID) in horses. One of the barriers associated with pergolide determinations in plasma for pharmacokinetic applications has been the technically demanding requirement for sensitivity. The objective of our work was to develop a simple assay for the determination of pergolide in plasma and demonstrate its potential application in the study of pergolide pharmacokinetics (PK) in horses. A UPLC-MS/MS assay was developed with a simple sample preparation involving methanol protein precipitation and injection of supernatant. The assay was applied to samples from a horse dosed with 10mg pergolide (as the mesylate salt) by nasogastric intubation. Plasma samples were collected over a 48h period. The assay demonstrated performance sufficient to enable application to low level PK studies. Within-batch precision and accuracy were within acceptance criteria; precision was less than 10% RSD (n=5) and accuracy was -7.3% at 0.014ng/mL, the lower limit of quantification was 0.006ng/mL and the method detection limit was 0.002ng/mL. In the treated horse, Cmax was 0.40ng/mL and the assay easily allowed determination of plasma levels in the elimination phase to 48h. In conclusion, this assay using UPLC-MS/MS and methanol protein precipitation easily meets the challenging demands of pergolide analyses in plasma.

The analysis of pergolide residues in horse plasma by LC with fluorescence detection.

Pergolide is used to treat pituitary pars intermedia dysfunction (equine Cushing's Disease), a neurodegenerative condition associated with loss of dopaminergic inhibition of the pituitary in horses. After oral administration, only low concentrations of the drug are achieved in plasma, making drug detection and quantification difficult. While direct analysis of plasma using sensitive MS/MS techniques is possible, dirty plasma samples and mobile phase buffers can cause instrumentation to become rapidly incapacitated. A method using LC with fluorescence detection was developed for pergolide analysis. LOQ for the instrumentation was 2 ng/mL when using direct injection of horse plasma samples, while interferences from the matrix were nominal. The use of SPE provided cleaner extracts and increased the LOQ in plasma samples to 0.15 ng/mL. The LC method developed allowed high sample throughput before pre-columns required replacement, which was extended when SPE cleanup was used. The effectiveness of SPE for the cleanup and preconcentration of plasma samples containing pergolide was demonstrated with spiked and naturally incurred samples; LC-MS/MS was used to validate the SPE method against direct injection samples.

Single-dose oral pharmacokinetics of pergolide mesylate in healthy adult mares.

Pituitary pars intermedia dysfunction (PPID) is probably the most common disease of geriatric horses. Affected horses show a variety of clinical signs, including hirsutism, polyuria/polydipsia, immunosuppression, muscle wasting, and laminitis. The most common treatment for PPID is pergolide, a dopamine agonist; however, there are no pharmacokinetic data about the use of this drug in horses. This article describes a study designed to address this complete lack of pharmacokinetic information. The pharmacokinetics of pergolide are described in a small group of relatively young, healthy mares (n = 6), with the objective of generating data on which to base larger studies in the future. To make definitive dosing recommendations to clinicians, more studies will be needed to investigate the relationship between plasma pergolide concentrations and clinical outcomes, as well as the effect of gender, age, and concomitant disease on the absorption and disposition of this drug.

High-sensitivity quantitation of cabergoline and pergolide using a triple-quadrupole mass spectrometer with enhanced mass-resolution capabilities.

Quantitative analysis of pharmaceuticals with low systemic plasma levels requires the utmost in sensitivity and selectivity from the analytical method used. A recently introduced triple-quadrupole mass spectrometer with unique enhanced mass-resolution capability was evaluated in the analysis of two such drugs, cabergoline and pergolide, in plasma. Liquid chromatographic/electrospray ionization selected reaction monitoring determination of cabergoline in plasma at unit mass-resolution demonstrated improved sensitivity (50 fg on-column), coupled with suitable accuracy and precision over a broad linear dynamic range covering five orders of magnitude (50 fg to 5 ng on-column). Liquid chromatographic/atmospheric pressure chemical ionization selective reaction monitoring determination of pergolide in plasma also attained a high level of sensitivity (500 fg on-column) at unit mass-resolution, with accuracy and precision values well within pharmaceutical industry standards. Again, a linear dynamic range covering five orders of magnitude (500 fg to 50 ng on-column) was achieved for the assay. Utility of the enhanced mass-resolution feature of the triple-quadrupole mass spectrometer in the determination of pergolide resulted in an improvement in analyte sensitivity (250 fg on-column) and linear dynamic range (250 fg to 50 ng on-column).

The pharmacokinetics of pergolide in Parkinson's disease.

Three decades of research have led to a fuller understanding of the pharmacokinetics of pergolide. Pergolide is rapidly absorbed following oral dosing, reaching peak plasma concentrations within 2-3 h. It is about 90% protein bound yet has negligible drug interactions. Pergolide undergoes extensive first-pass metabolism and is completely eliminated within 4-5 days. The metabolism/elimination profile varies between patients but is consistent within the individual, highlighting the importance of careful titration to an effective dose. Pergolide has a long half-life of about 21 h; this has interesting implications, as it should produce a more physiological or continuous stimulation of dopamine receptors, avoiding or delaying the induction of dyskinesia.

Sensitive, specific radioimmunoassay for quantifying pergolide in plasma.

Pergolide, a synthetic ergoline with potent dopaminergic activity, is used to treat Parkinson disease. The low plasma concentrations of pergolide achieved during therapy complicate the development of a method for its analysis. Because radioimmunoassay successfully measures other structurally related ergolines in physiological fluids, we undertook the development of a radioimmunoassay of pergolide. The detection limit of the radioimmunoassay is 21 ng/L with an optimal working range from 100 to 1000 ng/L. We maximized assay specificity by using a monoclonal antibody that displayed low cross-reactivity with pergolide sulfoxide, a major metabolite found in animals. The radioimmunoassay has performed acceptably for > 2 years during toxicology studies with rats and rhesus monkeys and in clinical studies involving patients with Parkinson disease. We consider the radioimmunoassay a valid method for quantifying therapeutic concentrations of pergolide in plasma.