McAllister R G, Tan T G
Pharmacology. 1980;20(2):95-100. doi: 10.1159/000137349.
Propranolol and verapamil are cardioactive drugs which may be useful during surgical procedures involving hypothermic cardiopulmonary bypass. Previous in vivo studies have shown that the pharmacokinetics of propranolol are altered by hypothermia, and that clearance of the drug is significantly reduced by lowered body temperature. Since both propranolol and verapamil are eliminated largely by hepatic metabolic activity, the effect of hypothermia on the ability of the liver to metabolize both drugs was studied in vitro with rat hepatic microsome preparations. Known quantities of the drugs were added after preincubation of microsomes at 37 degrees C (normothermia) or 26 degrees C (hypothermia), and the amount of drug substrate remaining after an additional incubation period was measured. Hypothermic microsomes metabolized significantly less of each drug at all substrate concentrations studies (p less than 0.001). Double-reciprocal plots showed similar results for experiments with both propranolol and verapamil: the extrapolated Vmax was the same for both temperature conditions, but the Km values were significantly increased by hypothermia (p less than 0.001), indicating reduced affinity for drug substrate by the microsomal enzymes. These in vitro studies show that hepatic metabolic elimination of both propranolol and verapamil is decreased by hypothermia.
普萘洛尔和维拉帕米是具有心脏活性的药物，在涉及低温体外循环的外科手术过程中可能有用。先前的体内研究表明，低温会改变普萘洛尔的药代动力学，体温降低会显著降低该药物的清除率。由于普萘洛尔和维拉帕米主要通过肝脏代谢活性消除，因此利用大鼠肝微粒体制剂在体外研究了低温对肝脏代谢这两种药物能力的影响。在微粒体于37℃（正常体温）或26℃（低温）预孵育后，加入已知量的药物，并测量在额外孵育期后剩余的药物底物量。在所有研究的底物浓度下，低温微粒体对每种药物的代谢均显著减少（p<0.001）。双倒数图显示，普萘洛尔和维拉帕米实验结果相似：两种温度条件下的外推Vmax相同，但低温使Km值显著增加（p<0.001），表明微粒体酶对药物底物的亲和力降低。这些体外研究表明，低温会降低普萘洛尔和维拉帕米的肝脏代谢消除。
