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

BACKGROUND Manipulation of forms of rectally administered metronidazole to improve bioavailability in horses has not been reported.

HYPOTHESIS/OBJECTIVES Evaluate the pharmacokinetics of 3 rectal metronidazole preparations compared to nasogastric (NG) administration.

ANIMALS Seven healthy horses.

METHODS Phase 1A was a randomized, 3-way crossover, single-dose pharmacokinetic study, and Phases 1B and 2 were non-randomized, single-dose follow-up studies. Metronidazole (20 mg/kg) was administered NG and rectally in water (RW20), as a rectal gel (RG), and in dimethyl sulfoxide (DMSO). Metronidazole (80 mg/kg) was also administered rectally in water (RW80) to 3 horses. Plasma concentrations were measured using liquid chromatography/tandem mass spectrometry. Pharmacokinetic variables were calculated, and predicted steady-state area under the curve (AUC0-24,ss) to minimum inhibitory concentration ratio was used as a pharmacodynamic target.

RESULTS Bioavailabilities for RW20 (33.7%), RG (2.49%), and DMSO (12.0%) were low relative to NG administration. When administered at a dosage of 20 mg/kg, only NG every 8 h was predicted to achieve the pharmacodynamic target in all horses. Administered rectally in water, the metronidazole maximum concentration increased from 3.11 +/- 0.63 μg/mL to 4.19 +/- 1.04 μg/mL when the dose was increased to 80 mg/kg. The RW80 predicted AUC0-24,ss for every 8 h administration was above target for all 3 horses.

CONCLUSIONS AND CLINICAL IMPORTANCE With the tested preparations, rectal administration of metronidazole at a standard dosage of 20 mg/kg yielded subtherapeutic plasma concentrations. Administering a 4-fold higher dose rectally in water might overcome these limitations. Oral and intravenous routes remain the preferred methods for administering metronidazole in horses.