Evaluation of orally and rectally administered misoprostol in a low-dose endotoxin challenge in horses

Abstract

Endotoxemia occurs in many equine diseases, resulting in systemic inflammatory response syndrome (SIRS). Misoprostol demonstrates in vitro reductions in pro-inflammatory cytokine production when stimulated by endotoxin. In vivo response is unknown. The objective of this study was to characterize the pharmacokinetics and pharmacodynamics of a single dose of misoprostol (5 µg/kg) administered orally (M-PO) or per rectum (M-PR) and to evaluate its effects on clinical inflammatory parameters when challenged with endotoxin intravenously (30 ng/kg IV). Horses and their treatment were randomized in a balanced 3x3 Latin square design for M-PR, M-PO, or control (CON) with minimum washout intervals of 28 days. Misoprostol plasma concentration, cytokine gene expression and production along with physical examination parameters, leukocyte counts, and blinded pain scores were obtained. Maximum plasma concentration (cmax) and area under the concentration-versus-time curve (AUC) were higher in M-PO treatment than M-PR treatment. Time to maximum concentration (tmax), disappearance half-life (t½), and mean residence time (MRT) were longer in M-PO compared to M-PR. Wide variations in cytokine gene expression and production were appreciated between horses. Subjectively, most prominent downregulation of cytokine gene expression occurred sooner in M-PR compared to M-PO. No statistically significant differences were appreciated between M-PR, M-PO, and CON for physical exam parameters, pain score, and cytokine protein production. Values of cmax obtained in this study were more than 8-fold higher than those previously reported in healthy horses. Future studies should investigate how prolonged systemic misoprostol exposure may affect these parameters, and a multi-dose administration study would benefit in optimizing dosage amount and intervals of misoprostol. Lastly, comparing pharmacokinetic differences between endotoxin-challenged and unchallenged conditions in the horses used in this study is warranted.