A study of structure-activity relationships in regard to species difference in the phenylbutazone series

Abstract

Physicochemical properties of phenylbutazone analogues were correlated with their physiological disposition, in particular with reference to species difference. While in man there exists a direct relationship between p Ka and half-life, no such correlation was observed in dogs. Half-life in dog appears to depend on factors such as fat/buffer partition coefficient (K p), plasma protein binding, tissue distribution and drug-metabolizing enzyme activity. Rate of metabolism of analogues, based on plasma level decline, varied extensively in both species. In man it ranged from 1 to 72 hr; in the dog from 0.5 to 33 hr. There are some striking species differences for certain compounds. For instance, oxyphen-butazone has a half-life of 0.5 hr in the dog whereas in man it is 72 hr. On the other hand, the half-life of G-15140 ( p, p′-dichloro analogue of phenylbutazone) is of the same order of magnitude for both species. An anomaly to the p Ka hypothesis, G-34208 (tertiary-butyl analogue of oxyphen-butazone, p Ka 7-1), has been shown to be excreted as a glucuronide. This conversion provides a ready explanation for the short half-life of G-34208, since glucuronides have p Ka values of about 3. Another sterically hindered analogue, G-13838 (isopropyi analogue of phenylbutazone), was found to have a volume of distribution twice that of phenylbutazone both in man and dog. The results are discussed in relation to the importance of these factors in the search for new drugs.