Perry S M, Whelan E, Shay S, Wood A J, Wood M
Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
Br J Anaesth. 1991 Jan;66(1):66-72. doi: 10.1093/bja/66.1.66.
We have studied the effect of i.v. anaesthesia with propofol in the emulsion (Intralipid) formulation on drug distribution and metabolism in six dogs using dual-route administration of propranolol as a model compound. Each dog was studied on two consecutive days: day 1 awake and day 2 during propofol anaesthesia (6 mg kg-1 followed by an infusion of 0.8 mg kg-1 min-1). Propofol anaesthesia was associated with reduced intrinsic clearance by 40% (P less than 0.05) but no significant difference in systemic clearance or hepatic plasma flow. Propofol produced marked changes in drug distribution; volume of distribution (Vss) of propranolol increased 54% from 82.5 (SEM 7.3) litre awake to 127.3 (27) litre during propofol anaesthesia (P less than 0.05). This change was accompanied by an increase (P less than 0.05) in the free fraction of propranolol from 8.5 (0.7) % in awake to 14.0 (0.7) % in propofol-anaesthetized dogs. The combination of the effects of both drug clearance and protein binding resulted in a 65% decrease in the intrinsic clearance of unbound drug (P less than 0.05). In contrast with the effects of propofol on drug distribution, infusion of Intralipid alone in another group of six dogs had no significant effects on drug distribution, protein binding or drug metabolism. We conclude that propofol is a modest inhibitor of drug metabolism, but has major effects on propranolol distribution, possibly by changing plasma protein binding.
我们使用普萘洛尔双途径给药作为模型化合物，研究了乳剂（英脱利匹特）剂型的丙泊酚静脉麻醉对6只犬药物分布和代谢的影响。每只犬连续两天接受研究：第1天清醒状态，第2天丙泊酚麻醉状态（6 mg·kg⁻¹，随后以0.8 mg·kg⁻¹·min⁻¹输注）。丙泊酚麻醉使内在清除率降低40%（P<0.05），但全身清除率或肝血浆流量无显著差异。丙泊酚使药物分布发生显著变化；普萘洛尔的分布容积（Vss）从清醒时的82.5（标准误7.3）升增加54%至丙泊酚麻醉时的127.3（27）升（P<0.05）。这种变化伴随着普萘洛尔游离分数的增加（P<0.05），从清醒时的8.5（0.7）%增加到丙泊酚麻醉犬的14.0（0.7）%。药物清除率和蛋白结合的综合作用导致未结合药物的内在清除率降低65%（P<0.05）。与丙泊酚对药物分布的影响相反，另一组6只犬单独输注英脱利匹特对药物分布、蛋白结合或药物代谢无显著影响。我们得出结论，丙泊酚是一种适度的药物代谢抑制剂，但对普萘洛尔分布有主要影响，可能是通过改变血浆蛋白结合来实现的。
