OXYGEN SUPPLEMENTATION RESTORES THEOPHYLLINE CLEARANCE TO NORMAL IN CIRRHOTIC RATS

Background/Aims: Capillarization associated with hepatic fibrosis may present a functional barrier to oxygen diffusion into the hepatocyte, and restriction on cellular oxygen supply may represent the rate-limit ing constraint on hepatic oxidative drug metabolism, The aim of this s tudy was to test this hypothesis by examining the effect of oxygen sup plementation on plasma theophylline clearance in 10 control and 10 cir rhotic rats, Methods: Theophylline (3 mg/kg) was administered intraven ously on two separate occasions, 24 hours apart, during which time the rats breathed either room air or oxygen (95%) from 1 hour before dosi ng until the end of plasma sampling with a randomized order of gas exp osure, Results: Theophylline clearance was significantly reduced by a mean of 37% (n = 10; P = 0.003) in cirrhotic rats compared with contro ls, Oxygen supplementation significantly improved plasma theophylline clearance in cirrhotic rats by a mean of 40% (n = 10; P = 0.007), wher eas clearance remained unchanged in healthy rats. Clearance in oxygen- supplemented cirrhotic rats was not significantly different from that in controls (P > 0.05), Conclusions: These novel findings indicate an important role for hepatic oxygenation in improving drug disposition i n cirrhosis, which may have potentially important clinical implication s for the management of this disease.