Effects of ketoconazole on the pharmacokinetics of doramectin in rabbits

This study aimed to investigate the influence of ketoconazole-mediated inhibition of P-glycoprotein (P-gp) on the pharmacokinetics of doramectin (DRM) administered orally and subcutaneously (SC) in rabbits. Twenty New Zealand rabbits were allocated into four groups (n = 5) and received DRM either orally or SC (0.2 mg/kg) alone or co-administered with ketoconazole (10 mg/kg PO, three doses at 12-hour intervals). Plasma, fecal, and urine samples were collected over 30 days to assess DRM concentrations. No significant differences were observed in the pharmacokinetic parameters of DRM between oral and SC administrations when given alone. However, co-administration with ketoconazole significantly altered DRM pharmacokinetics. The area under the plasma concentration–time curve (AUC₀–∞) was higher (p < 0.05) after oral DRM/ketoconazole treatment compared with oral DRM alone. Time to reach Cmax was shorter (p < 0.05), while elimination half-life (T1/2) and mean residence time (MRT) were prolonged (p < 0.05) in the presence of ketoconazole. Additionally, fecal DRM concentrations were reduced when DRM was administered with ketoconazole, either orally or SC, compared with DRM alone.Specifically, co-administration increased DRM AUC₀–∞ from 302.1 to 565.8 ng·day/mL (p = 0.003) and prolonged the elimination half-life from 42.5 ± 5.8 to 66.9 ± 6.1 h (p < 0.01). These findings indicate a clinically relevant pharmacokinetic interaction, likely due to inhibition of P-gp-mediated intestinal secretion, which may alter DRM’s antiparasitic efficacy and warrants caution when co-administering antifungal azoles with macrocyclic lactones. All animal procedures in this study were approved by the Research Ethics Committee of the Faculty of Veterinary Medicine, Delta University (Approval No. FPDU15/2025) and conducted in accordance with the ARRIVE guidelines. The findings provide practical insights for veterinary pharmacologists and rabbit producers regarding the safe co-administration of Doramectin and Ketoconazole, emphasizing potential pharmacokinetic interactions, appropriate withdrawal periods, and strict adherence to animal welfare and food safety regulations.