In isolated hepatocytes the availability of intracellular
glucose appears to be a key factor controlling the rate of
xenobiotic glucuronidation during
hypoxia. This study in the isolated perfused rat liver examines the effect of both a 24-hr fast and removal of
glucose (8 mM) from liver perfusate on the elimination of bolus doses of
harmol (20 mumol) under normoxic and hypoxic conditions. In the preparations used in these experiments,
harmol glucuronide is the major metabolite (greater than 80%) with the remainder being sulphate. During normal oxygenation, in the livers from fed rats,
harmol was rapidly eliminated (t1/2 = 4.2 +/- 0.4 min; mean +/- SD, N = 4). Fasting led to a small reduction in
harmol elimination rate (t1/2 = 5.6 +/- 0.4 min; P less than 0.025) while removal of
glucose from perfusate made no difference in either fed or fasted preparations. In the same livers, a second bolus dose of
harmol was given during
hypoxia. This produced a modest decline in
harmol elimination in fed rats (t1/2 = 7.1 +/- 2.0 min; P less than 0.05). However, in fasted rats there was a striking reduction in
harmol elimination (t1/2 = 109.8 +/- 54.0 min; P less than 0.025). The removal of
glucose from perfusate made no significant difference to these results (t1/2 = 253 +/- 209 min in fasted preparations, P greater than 0.1). In all preparations, reoxygenation resulted in a rapid recovery of drug elimination. We conclude that nutritional state is important in determining the impact of
hypoxia on
harmol elimination by the liver. This study suggests that clinically significant reductions in
xenobiotic glucuronidation are most likely to occur in poorly nourished or fasted subjects who became hypoxaemic.