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The bioavailability of metoclopramide was investigated in three steers following administration of 8 mg/kg by the oral, abomasal (cannula), and intravenous routes, using a Latin square design. The mean (+/- SD) oral and abomasal bioavailabilities were 51.3 +/- 30.7% and 76.2 +/- 15.5%, respectively. The mean value for clearance (Cl) was 20.1 +/- 5.9 ml/min and the volume of distribution (Vd) was 0.51 +/- 0.19 l/kg. Additional pharmacokinetic parameters for metoclopramide were determined following intravenous administration to seven cows. A predominate two-compartment model of distribution was found in six cows with a t 1/2 alpha harmonic mean of 24.2 min and a range of 11.2-72.4 min, a t 1/2 beta harmonic mean of 53.1 min and a range of 31.1-134.1 min, a Cl of 42.2 +/- 8.7 ml/min, and a Vd of 2.1 +/- 0.8 l/kg. To better define the relationship between metoclopramide concentration and release of prolactin, a treatment-by-subjects infusion study was conducted in which four different loading doses followed by constant infusion were used. A steady-state metoclopramide concentration (MCPss) of 8.8 +/- 2.6 ng/ml was associated with a three-fold elevation of prolactin to a mean value of 12.1 +/- 3.1 ng/ml in six yearling steers. Steady state serum prolactin concentrations (PRLss) did not rise significantly above 23.3 +/- 6.9 ng/ml, even when MCPss reached a concentration of 518.5 +/- 151.2 ng/ml. The short half-life, moderate Vd, low minimum pharmacologically effective concentration, and rapid Cl found for metoclopramide in cattle in this study, suggest that a continuous release device could potentially be useful in the application of this drug in the prevention and treatment of fescue toxicosis.

The dopamine antagonist metoclopramide monohydrochloride (MC) and the serotonin agonist quipazine maleate (Q) were administered to steers by both the oral and intravenous (i.v.) routes. Dose-response studies were designed to determine the effects of these drugs on serum prolactin (PRL) concentrations. Parameters subjected to analysis included maximal serum PRL concentrations within 1 h and the areas under the PRL response curves over time. At 1, 4, and 8 mg/kg i.v., and at 15, 30, 45, and 60 mg/kg orally, MC increased (P less than 0.05) serum PRL concentrations (difference between maximal and basal serum PRL concentrations) and increased (P less than 0.05) areas under the PRL response curves except for 1.0 mg/kg i.v. Doses of MC greater than 60 mg/kg and Q at all dosage rates were considered toxic. These studies determined a dose-response to MC in terms of serum PRL concentration and indicate that MC is well tolerated and effective for elevating serum PRL concentrations in steers. Furthermore, 4 mg/kg i.v. and 15 mg/kg orally could be considered the preferred dosage rates due to a plateau in the response above those rates.