Doramectin Percutaneous Absorption in Dogs: In Vivo and In Vitro Characterization

NEJAMKIN P; ALBARELLOS A; SALLOVITZ JM; LANUSSE CE

Congreso; 12th International Congress of the European Association for Veterinary Pharmacology and Toxicology; 2012

Introduction: Endectocides (avermectins and milbemycins) are important antiparasitic drugs owing to their wide spectrum of activity, high potency, safety margin and unique mode of action. They are mainly licensed for use in large animals and only few formulations have been approved to control endoparasites in companion animals. Due to its ease and practical administration, topical formulations have received great acceptance by [UTF-8?]petâ??s owners. However, limited information is available on dermal absorption and disposition of endectocides, particularly doramectin (DRM), in dogs. Time saving in vitro methods that allow characterising topical drug absorption and influence of different excipients are also lacking. The objectives of the present work were to characterize doramectin percutaneous permeation both in vivo and in vitro and to correlate in vivo absorption with in vitro permeation parameters.Materials and Methods: In vivo experiments: Six Beagles dogs were used in a cross-over design. In the first phase, three animals were treated intravenously (100 µg/kg) and other three topically (1000 µg/kg), after a 3-month washout period, in the second phase, animals were reversed. Blood samples were collected for up to 35 days post-administration in both experimental phases. In vitro experiments: Upper epidermis (500 µm thickness) slices of canine skin were prepared by using a dermatome and mounted on Franz-type diffusion cells (n=6). Doramectin was applied to the upper side of skin samples (2.8 mg/cm2) and, thereafter, receptor media were sampled up to 72 hours. Doramectin concentrations were determined by HPLC.Results: After its topical administration to dogs, DRM presented a Cmax of 4.31 ±2.14 ng/mL and Tmax of 5.25 ±3.18 days. Absolute bioavailability (F) was 2.34% ±086, the mean absorption time (MAT) 7.06 ±2.08 days and the mean elimination half-life 4.73 ±0.94 days. In vitro, the steady-state portion was observed between 14.7 ±7.4 and 60.0 ±17.2 hours post-administration. A 10.6 ±6.2 hours lag time (Tlag) was observed. Flux was of 1.5 ±1.2 ng/h/cm2 and permeability and diffusion coefficients (mean ±SEM) were 3.1x10-7 ±2.6x10-7 and 6.1x10-5 ±4.9x10-5, respectively. The correlation coefficients between in vivo absorption (partial AUC and percent absorbed) and in vitro permeation (percent permeated) up to 72 hours were 0.9833 and 0.9205 (Pearson r), respectively.Conclusions: This work described for the first time the percutaneous absorption of topical DRM both in vivo and in vitro. Topical DRM was absorbed through canine skin; however, due to its high lipophilicity, a skin depot of drug was observed. This is evidenced by the long absorption times (Tlag and MAT) and the low F obtained