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.