Effect of cold exposure on drug action and hepatic drug metabolism in the rat

Exposure of male rats to a temperature of 4°C for 4 days decreased the sleeping time response to hexobarbital and meprobamate, but not to barbital. Plasma concentrations of these drugs present at the time the righting reflex was regained were lower in the cold-exposed rats, indicating that the observed decrease in sleeping time was not due to decreased central nervous system sensitivity to these agents. The onset time of hexobarbital, meprobamate and barbital hypnosis was similar in cold-exposed and control rats, suggesting that altered drug absorption is not responsible for the observed differences in duration of drug response. The decline of brain and plasma concentrations of zoxazolamine was more rapid in the cold-exposed animal. The metabolism of hexobarbital and aminopyrine was significantly elevated in isolated perfused livers from cold-exposed rats. Hepatic microsomal N-demethylase activity, hexobarbital and meprobamate oxidation, CO-binding pigment, and NADPH-cytochrome c reductase activity were increased in the cold-exposed rat. Experiments with 2-¹⁴C-glycine indicated that the in vivo incorporation of this isotope into hepatic microsomes was increased significantly in the cold-exposed rat. These results indicate that cold exposure stimulates hepatic drug metabolism and suggest that this stimulation is mediated via an accelerated synthesis of the hepatic drug-metabolizing system.