Pharmacokinetic analysis and steady-state predictions of different preparations of metronidazole administered per rectum in adult horses.

Objective Overview

• This study investigated how three different rectal preparations of metronidazole (a common antibiotic) are absorbed and processed in horses compared to standard nasogastric (NG) administration.
• The research aimed to determine whether changing the form and dosage of rectally administered metronidazole could improve its bioavailability and potentially reach effective therapeutic levels.

Study Design and Methods

• Subjects: Seven healthy adult horses participated in the study.
• Study Phases:
  • Phase 1A: A randomized, 3-way crossover study where each horse received metronidazole through three rectal formulations and nasogastric route, allowing comparison within the same horses.
  • Phases 1B and 2: Non-randomized, single-dose follow-up studies to further explore promising results or test higher doses.
• Metronidazole Preparations Tested:
  • Rectal administration in water at 20 mg/kg (RW20)
  • Rectal gel (RG) at 20 mg/kg
  • Rectal administration in dimethyl sulfoxide (DMSO) at 20 mg/kg
  • Rectal administration in water at a higher dose of 80 mg/kg (RW80)—tested in 3 horses
  • Nasogastric (NG) administration at 20 mg/kg as control
• Measurement Techniques: Plasma metronidazole concentrations were measured using liquid chromatography/tandem mass spectrometry, a highly precise method for detecting drug levels.
• Pharmacokinetics and Pharmacodynamics:
  • Pharmacokinetic variables such as bioavailability and maximum plasma concentration (Cmax) were calculated.
  • The predicted steady-state concentration was evaluated through the area under the curve over 24 hours at steady state (AUC0-24,ss)
  • The ratio of AUC0-24,ss to minimum inhibitory concentration (MIC) was used as a pharmacodynamic target, indicating whether the drug concentration would likely be effective against pathogens.

Key Findings

• Bioavailability Results:
  • Rectal administration in water (RW20) had moderate bioavailability (33.7%) but still much lower than nasogastric route.
  • The rectal gel (RG) showed very poor bioavailability (2.49%), indicating almost no absorption through this preparation.
  • Rectal DMSO preparation had low bioavailability (12%), better than gel but still limited.
• Plasma Concentrations and Dosage Effects:
  • At 20 mg/kg, only nasogastric administration given every 8 hours reached therapeutic plasma levels in all horses.
  • Increasing the rectal dose in water to 80 mg/kg increased the maximum plasma concentration significantly (from ~3.11 to ~4.19 μg/mL).
  • This higher dose (RW80) predicted sufficient drug exposure (AUC0-24,ss above target) for effective therapy, despite being 4 times the standard dose.
• Therapeutic Implications:
  • Standard 20 mg/kg rectal dosing with the forms tested resulted in subtherapeutic drug levels—unlikely to be effective.
  • Rectal administration at much higher doses may overcome limited absorption but is not currently standard practice and requires further evaluation for safety and practicality.
  • Oral and intravenous administration remain the preferred routes for clinically reliable metronidazole delivery in horses.

Conclusions and Clinical Relevance

• The study confirms that metronidazole absorption in horses is substantially lower when administered rectally, especially for gel and DMSO formulations.
• Although rectal dosing in water shows better absorption, standard doses do not achieve therapeutic levels.
• A higher rectal dose could compensate for low bioavailability but needs careful consideration due to higher drug exposure and potential side effects.
• Veterinarians should prioritize oral or intravenous administration routes for metronidazole in horses to ensure effective treatment.
• This research fills an important knowledge gap about alternative routes of antibiotic administration in equine medicine and guides the development of improved dosing protocols.