Stimulation of mixed‐function oxidation of 7‐ethoxycoumarin in periportal and pericentral regions of the perfused rat liver by xylitol

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Abstract
Rates of O‐deethylation of 7‐ethoxycoumarin by perfused livers from fasted, phenobarbital‐treated rats were 3.7 μmol × g−1× h−1. Approximately 50% of the product was conjugated. When rates of 7‐ethoxycoumarin O‐deethylation were varied by infusing different concentrations of substrate, a good correlation (r= 0.91) was found between rates of O‐deethylation of 7‐ethoxycoumarin and fluorescence of 7‐hydroxycoumarin detected from the liver surface. Micro‐light guides (tip diameter 170 μm) placed on periportal and pericentral regions on the liver surface were used to monitor the conversion of nonfluorescent 7‐ethoxycoumarin to fluorescent 7‐hydroxycoumarin. The O‐deethylation of 7‐ethoxycoumarin to 7‐hydroxycoumarin increased fluorescence 64% and 28% in pericentral and periportal regions of the liver lobule, respectively. Rates of 7‐ethoxycoumarin O‐deethylation estimated from these increases in fluorescence were 5.2 μmol × g−1× h−1 in pericentral and 2.2 μmol × g−1× h−1 in periportal regions of the liver. During mixed‐function oxidation of 7‐ethoxycoumarin, the oxidation:reduction state of NADP(H) was similar in both regions of the liver lobule. Xylitol (2 mM) decreased the NADP+/NADPH ratio and stimulated rates of drug metabolism in both regions of the liver lobule. This indicates that conditions exist where the supply of NADPH is an important rate‐determining factor for 7‐ethoxycoumarin metabolism in both periportal and pericentral regions of the liver lobule.