Altered hepatic disposition of doxorubicin in the perfused rat liver at hyperthermic temperatures.

The perfused rat liver was used to study the effects of heat on hepatic functions and on the metabolism and biliary excretion of doxorubicin (Ad). Livers were perfused for 1 hour at 37 degrees C and 42 degrees C in the presence of biosynthetic substrates with or without Ad. Gluconeogenesis was decreased at both temperatures in the presence of Ad. Bile flow and excretion of Ad ceased at 42 degrees C. Perfusate levels of Ad were not significantly different in the 1-hour perfusions. Livers were then perfused at 37 degrees C and 41 degrees C for 3 hours in the presence of 10 mM glucose and amino acids. The beta half-life of Ad measured as total fluorescence and as parent drug was prolonged at 41 degrees C. The area under the plasma concentration-time curve was unchanged for parent drug but increased from 2010 micrograms/ml . min at 37 degrees C to 4477 micrograms/ml . min at 41 degrees C for total drug equivalents. Biliary excretion of total Ad equivalents was 7.39% +/- 1.35% of the total dose at 37 degrees C and 2.56% +/- 2.08% of the total dose at 41 degrees C (P less than 0.05). Biliary excretion of Ad was 2.07% +/- 0.37% of the total dose at 37 degrees C and 1.31% +/- 0.84% of the total dose at 41 degrees C (P less than 0.05). Hepatic tissue levels of total Ad equivalents were 288.7 +/- 21.2 micrograms/g at 37 degrees C and 322.7 +/- 10.6 micrograms/g at 41 degrees C (P less than 0.05). Tissue levels of Ad were 57.5 +/- 14 micrograms/g at 37 degrees C and 23.0 +/- 10.7 micrograms/g at 41 degrees C (P less than 0.05). Bile flow at the two temperatures decreased after 2 hours of perfusion. The greatest decrease in bile flow occurred during the third hour of perfusion at 41 degrees C. The data indicate that at elevated temperatures there was a significant alteration in the pharmacokinetics of Ad in the perfused rat liver system. Since the liver plays a primary role in the metabolism and elimination of Ad, the observed changes might also occur during wholebody hyperthermia.