Mechanism of Development of Tolerance to B-Diethylaminoethyl Diphenylpropylacetate (SKF 525-A) in the Rat

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Abstract
Summary Data presented here substantiate the early finding of Cook et al(1) that a tolerance develops to the hexobarbital prolonging effects of SKF 525-A in the rat. It is further shown that the biochemical correlates of this tolerance are an increased biosynthesis of ascorbic acid and an increased liver protein (enzyme) synthesis, which can be blocked by simultaneous administration of DL-ethionine. These observations are consistent with the action of several agents having the ability to stimulate drug metabolism (5). The mechanism of the tolerance, then, may be attributed to an induced metabolic alteration or adaptation to prolonged administration of SKF 525-A. Increased biosynthesis of ascorbic acid in animals repeatedly administered SKF 525-A indicates that impairment of ascorbic acid biosynthesis is not a related factor in the mechanism of action of this drug metabolism inhibitor.