A Single-Dose Pharmacokinetic Study of Metronidazole Administered to Gottingen Minipigs (Sus scrofa) by Oral Gavage or Voluntary Oral Dosing
Oral gavage (OG) dosing can be stressful to pigs and is associated with the risk of complications. To evaluate a potential refinement, we compared the pharmacokinetics of a drug with a known aversive taste (metronidazole) administered orally to 6 Gottingen minipigs with voluntary cooperation of the animal (voluntary oral [VO]) to 6 Gottingen minipigs dosed by OG. Blood was collected predose and at 0.5, 1, 2, 4, 8, and 24 h postdose and analyzed for drug concentration. Pharmacokinetic parameters for metronidazole were calculated, including Cmax, Tmax, AUC (from 0 to 24 h), and the ratios of AUC and Cmax between 2 dosing methods (AUC OG/VO ratio and Cmax OG/VO ratio, respectively). The time required to dose (dosing interval) and animal and staff acceptance of the dosing procedures were also assessed. All animals were dosed successfully, but one animal in each group was noted to have dosing difficulty. Mean dosing interval for OG dosing was greater than for VO (2.6 ± 0.24 min SD compared with 1.6 ± 0.36 min, respectively). VO dosing required fewer handlers, appeared to be less stressful to the animals, and was reported to be more ergonomically favorable than OG dosing. There were no significant differences in exposure including Cmax, Tmax, and AUC between OG and VO dosing. The OG/VO ratio was 1.27 for AUC and 1.25 for Cmax. Both animals with difficulty during dosing had pharmacokinetically inconsistent concentration–time profiles when compared with all other animals. These apparent differences were within the expected variability seen in pharmacokinetic studies. VO dosing may be a potential refinement for a single-dose pharmacokinetic study of an aversive tasting test material to minipigs.
Dosing interval for oral gavage compared with voluntary oral dosing of Gottingen minipigs. The time in minutes is shown between sequential dosing of animal test subjects for 2 methods of dosing (OG, oral gavage; VO, voluntary oral); n = 5 intervals between 6 animals. The horizontal bar represents the group mean. †, P ≤ 0.01
Pharmacokinetic parameters for metronidazole administered by oral gavage or voluntary oral dosing to Gottingen minipigs. Pharmacokinetic parameters are shown for metronidazole in minipigs dosed by 2 different methods (OG, oral gavage; VO, voluntary oral). The AUC shows 0 to 24 h. n = 6. The horizontal bar represents the group mean. Round markers indicate OG dosing. Square markers indicate VO dosing. Orange markers represent the individual animal in each group that experienced difficulty with dosing. There were no significant differences between means for Cmax, Tmax, or AUC (P > 0.05)
Individual pharmacokinetic curves for Gottingen minipigs dosed with metronidazole by oral gavage or voluntary oral dosing. Concentrations are shown of serum metronidazole at blood collection timepoints for individual animals dosed by 2 different methods. Solid markers indicate oral gavage dosing. Open markers indicate voluntary oral dosing. An asterisk indicates pharmacokinetically inconsistent concentration–time curves for a single animal in each group. Both animals had documented dosing difficulty.
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