EFFECT OF CHRONIC HYPOXIA ON ACETAMINOPHEN METABOLISM IN THE RAT

The effect of chronic hypoxia (10.5% O2 for 8-9 days) on acetaminophen metabolism was studied in vivo or in isolated cell or microsomal systems. Results from in vivo studies with oral administration of acetaminophen showed that in hypoxic rats, the plasma appearance of the drug was delayed and the plasma half-life was increased. Analyses of the area under the curve (AUC(oral)) showed that this value was higher in hypoxic rats, whereas the rate constants for elimination (k(elim)) and absorption (k(abs)) were lower in these animals. Formation of the glucuronide and sulfate conjugates was decreased significantly (P < 0.05) in hypoxic animals. The calculated volume of distribution (V(d)) after an intravenous dose was not different in either group but total clearance (CL) was 35% lower in hypoxic rats. Studies with isolated hepatocytes from both groups revealed that glucuronidation and sulfation were inhibited markedly at low O2 concentrations. The O2 concentrations required for half-maximal production (P50 values) of glucuronide (2.3-mu-M O2) and sulfate (1.8-mu-M O2) conjugates in cells from hypoxic animals were lower than for control cells (5.3-mu-M and 3.9-mu-M O2 for glucuronide and sulfate conjugates, respectively). Maximal rates of conjugation in cells from hypoxic rats were 60-70% of control rates. Similar decreases in microsomal UDP-glucuronosyltransferase and cytosolic sulfotransferase activities were found in livers of animals exposed to chronic hypoxia. These lower P50 values are consistent with a lower P50 for oxidation of mitochondrial cytochromes in hypoxic cells. In comparison, the P50 for glutathione conjugation (4.1-mu-M O2) was not statistically different from control (4.6-mu-M O2), but the maximal rate was 65% higher. The results show that chronic hypoxia causes a change of absorptive processes and decreased glucuronidation and sulfation reactions which affects the disposition of acetaminophen and potentially the disposition of a variety of other exogenous and endogenous compounds.