Plasma disposition, faecal excretion and in vitro metabolism of oxibendazole following oral administration in horses.

The research investigates the metabolism of the deworming drug, Oxibendazole (OBZ), in horses. The findings suggest that the first-pass metabolism process in horses significantly reduces the bioavailability of the drug. The study also showcases a potential approach to increase exposure of target parasites to the drug by inhibiting its metabolism using cytochrome P450 inhibitor – piperonyl butoxide.

Methodology

• The study involved oral administration of Oxibendazole (OBZ), a de-worming drug, to eight horses. The dosage was set at 10 mg kg(-1) of body weight for each horse.
• The researchers collected samples at various time points post administration to measure the presence of the drug and its metabolites in both plasma and faeces.

Results

• The parent OBZ could be detected in plasma only at 0.5 and 1.0 hours following administration, indicating that the drug was rapidly metabolized.
• The peak plasma concentration of OBZ was quite low (0.008 microg ml(-1)), hinting at its limited bioavailability.
• The parent OBZ was present in faeces between 12 and 72 hours after administration, the highest levels detected 24 hours post administration.
• An unidentified metabolite was found in the plasma from 0.5 to 72 hours post administration. This same metabolite was the second one to be detected during the in vitro study.

Role of Cytochrome P450 Inhibitor

• The OBZ metabolism in vitro was significantly decreased by co-incubation with a cytochrome P450 inhibitor, piperonyl butoxide.
• This suggests a potential avenue for prolonging OBZ exposure to nematodes (worms) by slowing down its metabolism using piperonyl butoxide.

Conclusions

• The study concluded that first-pass metabolism significantly limits the bioavailability of OBZ in horses. This means that a substantial amount of the orally administered drug is metabolically eliminated before it can effectively reach systemic circulation and exert its anthelmintic effect against worms.
• The presence of OBZ and its metabolite in faeces indicates that the drug is largely excreted through this route.
• Potentially, administering OBZ alongside a cytochrome P450 inhibitor such as piperonyl butoxide could slow the drug’s metabolism, thereby maximising the drug’s efficacy by extending the exposure of nematodes to the active compound.