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

Abstract

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.

Keywords: absorption; bioavailability; equine; flagyl; rectal.

Figure 1

Plasma metronidazole time-concentrations profiles for NG, RW20, RG, and DMSO administration at 20 mg/kg (n = 6). Mean ± SD are shown. Note, metronidazole concentrations were undetectable for all horses in the RW20 group at 48 h and in the RG group at 24 and 48 h. Thus, these data cannot be presented on a semilogarithmic plot. Abbreviations: NG = nasogastric; RW20 = rectal water at 20 mg/kg; RG = rectal gel; DMSO = dimethyl sulfoxide.

Figure 2

Comparison of t_1/2,z (A), T_max (B), C_max (C), AUC_0-∞ (D), and MRT (E) after NG, RW, and RG administration (20 mg/kg) in horses (n = 6). Statistically significant pairwise comparisons are shown. The bar represents the geometric mean for each group. Abbreviations: NG = nasogastric; RW20 = rectal water at 20 mg/kg; RG = rectal gel; MRT = mean residence time.

Figure 3

Plasma metronidazole concentration-time profiles after RW80 administration at 80 mg/kg in 3 horses. Abbreviation: RW80 = rectal water at 80 mg/kg.