P L Hickey1, P W Angus, A J McLean, D J Morgan. 1. Department of Pharmaceutics, Victorian College of Pharmacy, Monash University (Parkville Campus), Melbourne, Australia.
Abstract
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-limiting constraint on hepatic oxidative drug metabolism. The aim of this study was to test this hypothesis by examining the effect of oxygen supplementation on plasma theophylline clearance in 10 control and 10 cirrhotic rats. METHODS: Theophylline (3 mg/kg) was administered intravenously on two separate occasions, 24 hours apart, during which time the rats breathed either room air or oxygen (95%) from 1 hour before dosing until the end of plasma sampling with a randomized order of gas exposure. RESULTS: Theophylline clearance was significantly reduced by a mean of 37% (n = 10; P = 0.003) in cirrhotic rats compared with controls. Oxygen supplementation significantly improved plasma theophylline clearance in cirrhotic rats by a mean of 40% (n = 10; P = 0.007), whereas 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 in cirrhosis, which may have potentially important clinical implications for the management of this disease.
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-limiting constraint on hepatic oxidative drug metabolism. The aim of this study was to test this hypothesis by examining the effect of oxygen supplementation on plasma theophylline clearance in 10 control and 10 cirrhotic rats. METHODS:Theophylline (3 mg/kg) was administered intravenously on two separate occasions, 24 hours apart, during which time the rats breathed either room air or oxygen (95%) from 1 hour before dosing until the end of plasma sampling with a randomized order of gas exposure. RESULTS:Theophylline clearance was significantly reduced by a mean of 37% (n = 10; P = 0.003) in cirrhotic rats compared with controls. Oxygen supplementation significantly improved plasma theophylline clearance in cirrhotic rats by a mean of 40% (n = 10; P = 0.007), whereas 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 in cirrhosis, which may have potentially important clinical implications for the management of this disease.