DRUG METABOLISM IN HYPOTHERMIA. II. C¹⁴-ATROPINE UPTAKE, METABOLISM AND EXCRETION BY THE ISOLATED, PERFUSED RAT LIVER

¹ Department of Pharmacology, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania

The uptake, metabolism and excretion of C¹⁴-atropine by the isolated perfused rat liver were studied at 37°C and at two hypothermic temperatures, 25°C and 17°C. The uptake of C¹⁴-atropine by the liver was decreased from a half-time of 6 minutes to a half-time of 20 minutes as the temperature was decreased from 37 to 17°C. All of the C¹⁴ excreted into the bile appeared as atropine metabolites which were more polar than the parent compound. None appeared as unchanged atropine or as the hydrolysis product, tropic acid. A qualitative change in the relationship of the metabolites to one another was noted in the hypothermic preparations. A relatively unimportant metabolite at 37°C constituted a major portion of the biliary C¹⁴ activity in hypothermia, suggesting that the rate of transformation of this metabolite had been preferentially slowed. Other quantitative changes in the metabolite pattern are discussed. Within 4 hours, 60% of the injected dose of C¹⁴ appeared in the bile in the 37°C perfused preparation, 38% at 25°C and 14% at 17°C. The possible mode of C¹⁴ entry into the bile is considered. The effect of hypothermia on C¹⁴ excretion into the bile closely resembled that seen in the nephrectomized, bile fistula rat, but the latter was better able to maintain homeostasis at 25°C, while the reverse was true at 17°C.