Differential effects of hypoxia on the disposition of propranolol and sodium taurocholate by the isolated perfused rat liver.

Abstract

Although the adverse effect of hypoxia on drug metabolism is well documented in subcellular systems, its effect on drug clearance by the intact liver has not been defined. This study was undertaken in the isolated perfused rat liver to examine the effects of acute hypoxia on the hepatic elimination of two highly cleared substances--propranolol and sodium taurocholate. Hypoxia was established by equilibrating the perfusate with 100% nitrogen rather than 100% oxygen. This led to a fall in portal vein pO2 from 300 to 30 mm Hg, and a 10-fold rise in hepatic venous lactate:pyruvate ratio, indicating a profound alteration in hepatic cellular redox state. In bolus dose studies, propranolol uptake was unimpaired by hypoxia, with a monoexponential decline in perfusate concentrations from 2,000 to 30 ng per ml, (t1/2 uptake = 2.5 min). After 20 min of hypoxia, perfusate propranolol concentrations rose from 30 to 80 ng per ml, indicating release of propranolol from liver back into the perfusate. Reoxygenation of perfusate restored hepatic extraction of propranolol to normal (t1/2 uptake = 2.37 +/- 0.19 min vs. 2.55 +/- 0.60 min p greater than 0.1) such that perfusate concentrations were undetectable by 30 min. In steady-state studies, perfusate propranolol concentrations rose from 1.55 +/- 0.50 to 4.08 +/- 1.47 micrograms per ml (p less than 0.005), after 1 hr of hypoxia indicating a change in propranolol clearance from 15 ml per min to less than 6 ml per min. Reoxygenation resulted in a fall in perfusate propranolol concentrations towards control values (2.78 +/- 1.13 vs. 1.80 +/- 0.41 micrograms per ml, p greater than 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)