DRUG METABOLISM IN HYPOTHERMIA. UPTAKE, METABOLISM AND BILIARY EXCRETION OF PENTOBARBITAL-2-C¹⁴ BY THE ISOLATED, PERFUSED RAT LIVER IN HYPOTHERMIA AND EUTHERMIA

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

The isolated, perfused rat liver at 37°C is able to metabolize pentobarbital-2-C°¹⁴ at rates (2.4 µmol/g/hr) comparable to those reported for the intact rat. Under conditions of hypothermia, the rate of metabolism decreases to approximately onehalf (30°C), one-third (25°C) and one-fourth (20°C) the rate at 37°C, as estimated by the disappearance of unchanged pentobarbital from the blood. The net amount of C¹⁴ retained by the liver during the four-hour perfusion is the same at all temperatures, but the quantity of C¹⁴ excreted into the bile is markedly reduced in hypothermia, due primarily to the very pronounced decrease in bile flow. Bile/blood C¹⁴ concentration ratios never exceed 3 at any time on temperature after the administration of pentobarbital-2-C¹⁴. It therefore appears that the biliary route plays a minor role in the ultimate disposition of the drug and its metabolites. The metabolites formed by the liver are excreted mainly into the blood. A comparison is made between the disposition of pentobarbital-2-C¹⁴ and another weak acid (sulfanilamide) and two weak bases (atropine and procaine) previously studied under conditions of hypothermia in the isolated rat liver.