Pharmacokinetic features of metochlopramide in rabbits after different routes of administration

To assess the pharmacokinetics (PK) of metochlopramide (MET) in rabbits after different routes of administration. Six normal, male, white New Zealand rabbits weighing 3.0‐3.5 kg were involved in the study. Animals were randomly assigned to four treatment groups, using an open, single‐dose, 4‐treatment, 4‐period, unpaired, cross‐over design (4x4 Latin‐square). Animals in group I (n=2) received a single dose of 2 mg/kg of MET injected intravenously (IV) into the left marginal ear vein. Group II (n=2) received the same dose but by intramuscular (IM) route, injected in the middle quadrant of the buttock muscle. Group III (n=1), received the same dose via sub‐cutaneous (SC) administration. Group IV (n=1), received a single dose of 4 mg/kg via per‐rectum (PR) administration. The washout period was 1 week. The groups were rotated, changed in subject number and the administrations repeated. The blood (2 mL) was collected via indwelling catheter implanted in the central artery of the ear, at assigned times (0, 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 4 and 6 hr). After four weeks, each rabbit had been administered with MET by the four routes. The HPLC analyses were carried out according to Giorgi et al (1) shortly revalidated in rabbits. The PK analysis was carried out according to a non‐compartmental (WinnonLin 5.3). Followig IV administration the resulting plasma concentrations declined rapidly over the first hour and became undetectable after 4 hr. After the IM and SC treatments the plasma drug concentrations were below the LOQ of the method after 4 hr, while in the PR group only 2 out 6 animals showed detectable plasma concentration up to 4 h. The IM and SC administrations gave matching pharmacokinetic profiles, overlapping in the elimination phase with the IV curve (figure). MET was fastly absorbed (Tmax 0.19 min in both SC and IM groups, and 0.26 min in the PR group) and eliminated. All groups showed a short half life (0.81, 0,89 1.01 and 1.67 hours, in IM, SC, IV and PR administrations, respectively). The SC and IM bioavailabilities were high (112.0% and 96.2%, respectively), while the PR bioavailability was about 12.2%. This might be triggered by the sequestration of drug in fecal matter. The results of the present study suggest that the IM and SC administrations of MET could be useful in treating gastrointestinal motility disorder in rabbits when a venous access is not available. The PR administration is likely to be unrealiable.