Kidney metabolism of acetaminophen and phenacetin

The metabolism of acetaminophen and phenacetin by rabbit kidney slices was investigated. Phenacetin, like aspirin, inhibited [131I] Hippuran accumulation by the organic acid transport system. Phenacetin exhibited a dose-dependent inhibition with a K1 of 0.5 mM; acetaminophen at concentrations as high as 1 mM did not alter organic acid transport. [3H] acetaminophen slice: media ratios of approximately 1 or less suggested that acetaminophen entered cortex and outer and inner medullary slices by diffusion rather than active transport. Approximately 95% of the acetaminophen within the slices readily diffused out into the media. The chromatographic patterns of this material were similar to that of the incubation media. The acetaminophen remaining within the slices was acid-precipitable and not extractable with organic solvents. This covalent binding of acetaminophen was inhibited by glutathione. More acetaminophen was bound in the renal medullar than cortex. These data suggest that the renal metabolism of acetaminophen observed in this in vitro study may be related to the nephritis observed in analgesic abuse.