Yeleswaram K, Rurak D W, Kwan E, Hall C, Doroudian A, Abbott F S, Axelson J E
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Drug Metab Dispos. 1993 Mar-Apr;21(2):284-92.
Labetalol causes significant maternal and fetal metabolic effects in pregnant sheep (Yeleswaram et al., J. Pharmacol. Exp. Ther. 262, 683-691 (1992)). This study was undertaken to investigate the contribution of skeletal muscles in the development of metabolic acidosis induced by labetalol and to explore the involvement of active metabolite(s) using conscious, chronically instrumented adult nonpregnant ewes. Following a 100 mg iv bolus, the disposition of labetalol was similar to that observed in pregnant sheep. The effects of labetalol included hypotension, reflex tachycardia, a significant increase in femoral blood flow, hyperglycemia, lactic acidosis, and increased hind limb oxygen consumption. The arteriovenous flux of labetalol, glucose, lactate, and oxygen across the hindlimb was calculated using the Fick principle. The net output of lactate from the hindquarter over 12 hr following drug administration was calculated to be 6.25 +/- 1.35 g (0.07 +/- 0.015 mol). Glucuronidation, sulfation, and oxidative metabolism of labetalol were studied using urine and bile samples. The cumulative urinary excretion of labetalol as unchanged drug, glucuronide and sulfate was found to be 1.61 +/- 0.3, 11.46 +/- 2.83, and 1.47 +/- 0.74% of the dose, respectively. Using GC-mass selective detection, the presence of 3-amino-1-phenylbutane (3-APB), a close congener of amphetamine, in urine and bile samples was established. The cumulative excretion of 3-APB in urine represents 0.044 +/- 0.016% of the dose. Pharmacokinetic analysis shows the apparent elimination half-life of the metabolite to be 13.5 +/- 3.8 min. Conjugates of 3-APB were also found in the bile and urine.(ABSTRACT TRUNCATED AT 250 WORDS)
拉贝洛尔可对妊娠绵羊的母体和胎儿产生显著的代谢影响（耶莱斯瓦拉姆等人，《药理学与实验治疗学杂志》262卷，683 - 691页（1992年））。本研究旨在调查骨骼肌在拉贝洛尔诱导的代谢性酸中毒发展过程中的作用，并使用清醒的、长期植入仪器的成年非妊娠母羊来探究活性代谢物的参与情况。静脉推注100毫克拉贝洛尔后，其处置情况与在妊娠绵羊中观察到的相似。拉贝洛尔的作用包括低血压、反射性心动过速、股血流量显著增加、高血糖、乳酸酸中毒以及后肢氧消耗增加。使用菲克原理计算拉贝洛尔、葡萄糖、乳酸和氧气在后肢的动静脉通量。给药后12小时内后肢乳酸的净输出量经计算为6.25±1.35克（0.07±0.015摩尔）。使用尿液和胆汁样本研究了拉贝洛尔的葡萄糖醛酸化、硫酸化和氧化代谢。拉贝洛尔以未变化药物、葡萄糖醛酸苷和硫酸盐形式的累积尿排泄量分别为给药剂量的1.61±0.3%、11.46±2.83%和1.47±0.74%。使用气相色谱 - 质量选择性检测法，确定了尿液和胆汁样本中存在苯丙胺的类似物3 - 氨基 - 1 - 苯基丁烷（3 - APB）。尿液中3 - APB的累积排泄量占给药剂量的0.044±0.016%。药代动力学分析表明该代谢物的表观消除半衰期为13.5±3.8分钟。在胆汁和尿液中也发现了3 - APB的结合物。（摘要截取自250字）
