To examine the validity of extrapolating parenteral product bioequivalence determinations across target animal species, the relative bioavailability of two injectable formulations of ampicillin trihydrate (PolyflexR, a water-based suspension, and Ampi-kel 10R, an oil-based suspension) was examined in calves, sheep and swine. Employing products recognized to be bioinequivalent provided an opportunity to explore potential species-by-formulation interactions. As compared with PolyflexR, Ampi-kel 10R exhibited lower area under the curve (AUC) estimates but higher peak concentrations in all target animal species. Nevertheless, marked interspecies differences were noted in the width and bounds of the confidence intervals about the differences in treatment means. Potential physiological and physico-chemical reasons for these findings are discussed.
Phenylbutazone was administered intravenously (i.v.) to a group of four lactating cows at a dosage of 6 mg/kg body weight. Whole plasma, protein-free plasma and milk were analysed for phenylbutazone residues. Pharmacokinetic parameters of total and free phenylbutazone in plasma were calculated using a non compartmental method. In regards to whole plasma data, the mean volume of distribution at steady state (Vss), was 147 mL/kg body weight, with a mean (+/-SEM) terminal elimination half-life (t1/2) of 40+/-6 h. The mean clearance (Cl) was 3 mL/h/kg body weight. The Vss as determined from the protein-free plasma fraction was 50021 mL/kg body weight. This larger Vss of free phenylbutazone compared to total plasma phenylbutazone was attributed to a high degree of plasma protein binding, as well as the greater penetration of free phenylbutazone into tissues. The mean t1/2 of free phenylbutazone was 39+/-5 h. This similarity to the t1/2 estimated from total plasma phenylbutazone data is attributed to an equilibrium between free and plasma phenylbutazone during the terminal elimination phase. Mean t1/2 as determined from milk, applying a urinary excretion rate model, was 47+/-4 h. Milk clearance of phenylbutazone was 0.009 mL/h/kg body weight, or about 0.34% of total body clearance. Furthermore, evidence suggests that phenylbutazone either binds to milk proteins, or is actively transported into milk, as its concentration in milk was greater than that predicted due to a simple partitioning from plasma into milk.
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