Effect of hypothermia on drug metabolism. In vitro studies with propranolol and verapamil.

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.