The disposition of diphenhydramine and four of its analogues in rabbits and implication for structure-activity relationship studies in drug design.
The disposition of diphenhydramine (I) and four of its ring substituted analogues, 4-bromodiphenhydramine (II), 4-methyldiphenhydramine (III), 2-methyldiphenhydramine (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 less than IV less than III less than II less than V and volume of distribution in the order III less than 1 less than IV less than V less than 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.
D000818:Animals; D004155:Diphenhydramine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism*; D007263:Infusions, Parenteral; D008297:Male; D011817:Rabbits; D013329:Structure-Activity Relationship; D013997:Time Factors
D004155:Diphenhydramine