Norman W M, Court M H, Greenblatt D J
Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville 32610-0136, USA.
Am J Vet Res. 1997 Aug;58(8):878-80.
To evaluate changes in the pharmacokinetic disposition of diazepam in foals from 4 to 84 days of age.
4 male and 2 female full-term mixed-breed foals.
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 i.v. administration of 0.25 mg of diazepam/kg of body weight to foals at 4, 21, 42, and 84 days of age.
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.
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 determines whether diazepam will accumulate with repeated doses, and care should be taken when administering repeated doses to foals < 21 days old.
评估4至84日龄马驹地西泮药代动力学处置的变化。
4匹雄性和2匹雌性足月混血马驹。
在4日龄、21日龄、42日龄和84日龄的马驹静脉注射0.25 mg地西泮/千克体重后，测定地西泮的终末半衰期、分布容积、清除率、游离分数、非结合分布容积、游离清除率、去甲地西泮峰值浓度以及去甲地西泮浓度-时间曲线下面积。
地西泮的处置情况用二室模型描述最佳。4日龄时测定的清除率和游离分数值（均值±标准误）（分别为5.06±0.79和51±8 ml/千克/分钟）显著低于21日龄（8.64±0.95和87±11 ml/千克/分钟）、42日龄（7.31±0.82和83±10 ml/千克/分钟）和84日龄（8.41±0.56和100±12 ml/千克/分钟）时的测定值。4日龄时测定的分布容积和非结合分布容积值（分别为1.57±0.11和16.0±1.7 L/千克）显著低于21日龄（2.66±0.33和26.8±3.9 L/千克）、42日龄（3.00±0.42和33.9±5.0 L/千克）和84日龄（2.55±0.35和30.2±5.3 L/千克）时的测定值。4日龄时获得的血浆去甲地西泮峰值浓度（22.7±2.4 ng/ml）显著低于21日龄（36.1±4.5 ng/ml）、42日龄（38.3±4.8 ng/ml）和84日龄（34.6±2.1 ng/ml）时的测定值。
可能影响马驹地西泮药代动力学处置的因素，如身体组成和肝酶活性，在出生后的前21天处于变化中。这些因素对地西泮清除率和分布容积有相反的影响，因此终末半衰期保持不变。然而，清除率决定了地西泮是否会随着重复给药而蓄积，对21日龄以下的马驹重复给药时应谨慎。
