Multi-dose misoprostol pharmacokinetics and its effect on the fecal microbiome in healthy, adult horses

Abstract

Misoprostol, a synthetic prostaglandin E1 (PGE1) analogue, is administered to treat glandular gastric ulcers in horses and may possess anti-inflammatory properties. However, misoprostol’s multi-dose pharmacokinetics and effects on the fecal microbiome in horses require investigation. Our objectives were to compare the pharmacokinetics between repeated doses and to characterize changes in the fecal microbiome after oral and rectal multi-dose misoprostol administration in 6 healthy university-owned geldings. In a randomized, cross-over study, misoprostol (5 g/kg) was administered orally or rectally every 8 hours for 10 doses, or not administered (control), with a 21-day washout between treatments. Concentration-versus-time data for dose 1 and dose 10 were subject to non-compartmental analysis. For microbiota analysis using 16sRNA amplicon sequencing, manure was collected at -7 days, immediately prior to dose 1, then 6 hours, 7 days, and 14 days after dose 10, with time-matched points in controls. Repeated dosing related differences in pharmacokinetic parameters were not detected for either administration route. Area under the concentration-versus-time curve was greater (p < 0.04) after oral versus rectal administration. Relative bioavailability of rectal administration was 4-86% that of oral administration. Microbial composition, richness, and β-diversity differed among subjects (p < 0.001 all) while only composition differed between treatments (p ≤ 0.01). Richness was decreased 6 hours after dose 10 and at the control-matched timepoint (p = 0.0109) in all subjects. No other differences for timepoints, treatments, or their interactions were observed. Overall, differences in systemic exposure were associated with route of administration, but were not detected after repeated administration of misoprostol. Differences in microbiota parameters were primarily associated with inter-individual variation and management rather than misoprostol administration.