The Oxygen Diffusion Barrier Hypothesis states that aging in the liver is associated with restricted oxygen uptake that explains the age-related impairment of phase I drug clearance observed in vivo with preservation of in vitro phase I enzyme activity and in vivo phase II drug clearance. Aging in the liver may be secondary to oxidative stress. Therefore we examined the effects of oxidative injury on oxygen uptake, and phase I and phase II drug metabolism in the liver. Oxidative stress was induced in the perfused rat liver with hydrogen peroxide. The intrinsic clearances of propranolol and morphine were used as markers of phase I and phase II activity, respectively. Oxidative injury was associated with a 14+/-99% (P=0.03) reduction in oxygen uptake. The decrease in the intrinsic clearance of propranolol was greater than that of morphine (57+/-14% vs 34+/-7% P<0.005). This result supports the concept of a restriction of oxygen supply constraining hepatic drug metabolism following oxidative stress. This has implications for aging and hepatic drug metabolism.