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.