The disposition of diphenhydramine and four of its analogues in rabbits and implication for structure‐activity relationship studies in drug design

Publisher Website
Google Scholar
Abstract
The disposition of diphenhydramine (I) and four of its ring substituted analogues, 4‐bromodiphenhydramine (II), 4‐methyldiphenhydramine (III), 2‐methyldiphen‐hydramine (IV), and 4‐t‐butyldiphenhydramine (V), was investigated in the rabbit, during and after intravenous infusion. The concentration of each analogue was determined by gas‐liquid chromatography (GLC) and the disposition parameters of clearance, volume of distribution, and elimination rate constant determined. These parameters were found to vary within the series, clearance increased in the order I < IV < III < II < V and volume of distribution in the order III < I < IV < V < II. These changes correlated with the Hansch hydrophobic substituent parameter: for clearance r = 0.97, for volume r = 0.7. The implication of these changes for the design of studies investigating the effects of structure on pharmacological response are discussed.