Court M H, Greenblatt D J
Department of Surgery, Tufts University, School of Veterinary Medicine, North Grafton, Massachusetts.
J Vet Pharmacol Ther. 1992 Dec;15(4):343-50. doi: 10.1111/j.1365-2885.1992.tb01026.x.
The pharmacokinetics of midazolam were investigated following intravenous and intramuscular administration of 0.5 mg of midazolam hydrochloride/kg of body weight to five healthy mixed-breed dogs. One dog also received the same dose of midazolam by oral and rectal routes. The disposition of midazolam following intravenous administration was characterized by very rapid and relatively extensive distribution followed by rapid elimination. Mean (+/- SD) apparent volume of distribution was 3.0 +/- 0.9 l/kg, mean elimination half-life was 77 +/- 18 min, and clearance was 27 +/- 3 ml/kg/min. Following intramuscular administration, absorption was rapid and complete. A mean peak midazolam concentration of 549 +/- 121 ng/ml was reached within 15 min, and systemic availability was over 90% in each dog. Oral administration to one dog resulted in peak midazolam concentrations within 10 min and a systemic availability of 69%. Rectal administration to the same dog yielded very low systemic availability. Midazolam was extensively bound to canine plasma proteins, with the unbound fraction representing less than 4% of the total plasma midazolam concentration. Plasma samples were also assayed for the presence of the major metabolites, 1-OH and 4-OH midazolam. Neither metabolite were detected, probably as a result of rapid elimination of these compounds by hepatic glucuronidation. Behavioral responses to administration of midazolam included initial signs of profound weakness, ataxia and transient agitation followed by a period of quiesence. A normal behavior pattern returned within 2 h of midazolam administration.
给五只健康的杂种犬静脉注射和肌肉注射每千克体重0.5毫克盐酸咪达唑仑后，对咪达唑仑的药代动力学进行了研究。一只犬还通过口服和直肠途径接受了相同剂量的咪达唑仑。静脉注射后咪达唑仑的处置特点是分布非常迅速且相对广泛，随后迅速消除。平均（±标准差）表观分布容积为3.0±0.9升/千克，平均消除半衰期为77±18分钟，清除率为27±3毫升/千克/分钟。肌肉注射后，吸收迅速且完全。在15分钟内平均咪达唑仑峰值浓度达到549±121纳克/毫升，每只犬的全身生物利用度超过90%。对一只犬口服给药后，咪达唑仑在10分钟内达到峰值浓度，全身生物利用度为69%。对同一只犬直肠给药产生的全身生物利用度非常低。咪达唑仑与犬血浆蛋白广泛结合，未结合部分占血浆中咪达唑仑总浓度的不到4%。还对血浆样本检测了主要代谢物1-羟基咪达唑仑和4-羟基咪达唑仑的存在情况。两种代谢物均未检测到，可能是由于这些化合物通过肝脏葡萄糖醛酸化迅速消除的结果。给予咪达唑仑后的行为反应包括最初出现深度虚弱、共济失调和短暂躁动的迹象，随后是一段安静期。在给予咪达唑仑后2小时内恢复正常行为模式。
