Bioavailability and pharmacokinetics of metoclopramide in cattle

Abstract

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.

Ultrasonographic assessment of the reticular motility in cows after administration of different doses of metoclopramide and neostigmine

“…It is suggested that metoclopramide at 0.3 mg/kg could produce mild and transient prokinetic effect. This finding supports the result of Jones et al (1994) that recorded short half-life of metoclopramide and suggested use continuous release device to produce prolonged effect. Metoclopramide is an antagonist at dopaminergic (D2) receptors and a serotonin (5-hydroxytryptamine; 5-HT) agonist at 5-HT4 receptors and antagonist at 5-HT3 receptors (Plaza et al 1996).…”

“…Similar finding was recorded in goat by Huhn et al (1992) and Huhn and Nelson (1997) who found that a biological half-life of metoclopramide was 0.62 h and the serum concentrations following IM administration of 0.5 mg/kg rose rapidly to a peak of 160.9 ng/ml at 15 min post-dosing and then declined in parallel with the elimination phase of the IV. The effect of the drug lasted for short period and the recorded changes disappeared at 40 minutes suggesting its effect is transient, the finding, which support the previous results that conclude the short half-life, and low minimum pharmacologically effective concentration, and rapid clearance for metoclopramide in cattle (Jones et al 1994). It is suggested that metoclopramide at 0.3 mg/kg could produce mild and transient prokinetic effect.…”

“…Neither heart nor respiratory rates were significantly affected. Excitement followed by depression and somnolence has been observed in cattle and goats after administration of metoclopramide at doses ≥0.3 mg/kg (Zdelar et al 1979;Jones et al 1994;Huhn and Nelson 1997) Taken together, these findings suggest that metoclopramide (0.3 mg/kg, IM) may exert a weak prokinetic effect in ruminants, but associated with the occurrence of adverse behavioral effects. Moreover, Guard et al (1988) recorded behavioral changes in calves after administration of metoclopramide.…”

Biowaiver Monographs for Immediate Release Solid Oral Dosage forms: Metoclopramide Hydrochloride

“…28 Another source reports the BA of oral metoclopramide to be about 75%, but varying between approx 30% and 100%. 14 Other sources report values of 51% (standard deviation: 31%), 40 32-97%, 41 77%, 42 and 68% (standard deviation: 13%). 43 This wide range in BA has been attributed to the interindividual variable first-pass effect.…”

Identification of metoclopramide metabolites in the urine of cattle by gas chromatography-mass spectrometry and high-performance liquid chromatography-photodiode array detection

“…The synthetic scheme and structures of metoclopramide and some synthesized metabolites are shown in Figure LA-F. The bioavailability and pharmacokinetic parameters of metoclopramide have been investigated in steers and cows (Jones et aL, 1993) using an HPLC assay (Jones and Bowen, 1991). Previous studies have identified eight metabolites in the rat, four in the dog, and three in human urine, with 2-[(4-amino-5-chloro-2-methoxybenzoyl)amino]acetic acid being the only common metabolite (Bakke and Segura, 1976;Teng et al, 1977).…”