Sams R A, Detra R L, Muir W W
Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Ohio State University Colmbus 43210, USA.
Equine Vet J Suppl. 1992 Feb(11):45-51. doi: 10.1111/j.2042-3306.1992.tb04772.x.
The pharmacokinetics and metabolism of doxapram in horses administered intravenous (iv) doses of 0.275, 0.55 and 1.1 mg doxapram/kg bodyweight (bwt) were investigated. Plasma doxapram concentrations decreased rapidly after drug administration and the disappearance of doxapram from plasma was best described by a polyexponential equation. Median values of total body clearance were 10.9, 10.6 and 10.9 ml/min/kg bwt for the three doses and were independent of dose. The steady-state volume of distribution was approximately 1,200 ml/kg bwt and the median biological half-life ranged from 121 to 178 mins. Plasma protein binding of doxapram ranged from 76.0 to 85.4 per cent. The blood:plasma doxapram concentration ratio was approximately 0.8 and the affinity of the red blood cells for doxapram ranged from 2.0 to 2.8 indicating sequestration of doxapram in erythrocytes. Renal clearance of doxapram was a minor route of elimination. Metabolic clearance of doxapram appeared to be a major route of elimination. Four metabolites of doxapram were isolated from urine and were identified. The metabolites were: a) 1-ethyl-4-[(2-hydroxyethyl) amino]ethyl-3,3-diphenyl-2-pyr-rolidinone, b) a glucuronic acid or sulphuric acid conjugate of 1-ethyl-3-(hydroxyphenyl)-4-(2-morpholinoethyl)-3-phenyl-pyrrolidinone, c) 3,3-diphenyl-4-(2-morpholinoethyl)-2-pyrrolidinone and d) 1-(2-hydroxyethyl)-3,3-diphenyl-4-(2-morpholinoethyl)-2-pyr-rolidinon e. The rapid disappearance of doxapram from plasma immediately after iv administration was attributed to redistribution of the drug from plasma to other tissues. The short duration of clinical effect from doxapram may be attributed to redistribution of the drug from plasma and other well-perfused tissues, such as the brain, to less well-perfused tissues such as the skeletal muscles and adipose tissue. Continuous or repeated administration of doxapram could prolong the duration of clinical effect because re-distribution is less important as steady-state conditions are approached.
研究了静脉注射剂量为0.275、0.55和1.1毫克多沙普仑/千克体重的马匹体内多沙普仑的药代动力学和代谢情况。给药后血浆多沙普仑浓度迅速下降，血浆中多沙普仑的消失情况用多指数方程描述最为合适。三个剂量的总体清除率中位数分别为10.9、10.6和10.9毫升/分钟/千克体重，且与剂量无关。稳态分布容积约为1200毫升/千克体重，中位生物半衰期为121至178分钟。多沙普仑的血浆蛋白结合率在76.0%至85.4%之间。血药浓度与血浆浓度之比约为0.8，红细胞对多沙普仑的亲和力在2.0至2.8之间，表明多沙普仑在红细胞中被隔离。多沙普仑的肾清除是次要的消除途径。多沙普仑的代谢清除似乎是主要的消除途径。从尿液中分离并鉴定出了多沙普仑的四种代谢产物。这些代谢产物分别为：a）1-乙基-4-[(2-羟乙基)氨基]乙基-3,3-二苯基-2-吡咯烷酮，b）1-乙基-3-(羟苯基)-4-(2-吗啉代乙基)-3-苯基-吡咯烷酮的葡萄糖醛酸或硫酸酯共轭物，c）3,3-二苯基-4-(2-吗啉代乙基)-
