Age-related changes in the pharmacokinetic disposition of diazepam in foals

Abstract

Objective - To evaluate changes in the pharmacokinetic disposition of diazepam in foals from 4 to 84 days of age. Sample Population - 4 male and 2 female fullterm mixed-breed foals. Procedure - Diazepam terminal half-life, volume of distribution, clearance, free fraction, unbound volume of distribution, free clearance, peak desmethyldiazepam concentration, and area under the desmethyldiazepam concentration-time curve were determined after IV administration of 0.25 mg of diazepam/kg of body weight to foals at 4, 21,42, and 84 days of age. Results - Disposition of diazepam was best described using a two-compartment model. Clearance and free fraction values (mean ± SEM) determined at 4 days (5.06 ± 0.79 and 51 ± 8 ml/kg/min, respectively) were significantly less than those obtained at 21 (8.64 ± 0.95 and 87 ± 11 ml/kg/min), 42 (7.31 ± 0.82 and 83 ± 10 ml/kg/min), and 84 (8.41 ± 0.56 and 100 ± 12 ml/kg/min) days. Volume of distribution and unbound volume of distribution values determined at 4 days (1.57 ± 0.11 and 16.0 ± 1.7 L/kg, respectively) were significantly less than those found at 21 (2.66 ± 0.33 and 26.8 ± 3.9 L/kg), 42 (3.00 ± 0.42 and 33.9 ± 5.0 L/kg), and 84 (2.55 ± 0.35 and 30.2 ± 5.3 L/kg) days. Peak plasma desmethyldiazepam concentration obtained at 4 days (22.7 ± 2.4 ng/ml) was significantly lower than that obtained at 21 (36.1 ± 4.5 ng/ml), 42 (38.3 ± 4.8 ng/ml), and 84 (34.6 ± 2.1 ng/ml) days. Conclusions - Factors likely to affect the pharmacokinetic disposition of diazepam in foals, such as body composition and hepatic enzyme activity, are in transition during the first 21 days of life. These have opposing effects on diazepam clearance and volume of distribution so that terminal half-life remains unchanged. However, clearance deter mines whether diazepam will accumulate with repeated doses, and care should be taken when administering repeated doses to foals < 21 days old.