A kinetic study of the antihistaminic effect of terfenadine

Kinetics of the antihistaminic effect of alpha-[4-(1,1-dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-1- piperidinebutanol (terfenadine, RMI 9918, Triludan, Teldane, resp.) were examined in the isolated guinea pig ileum and spirally cut tracheal strip preparations. In the isolated guinea pig ileum, terfenadine produced a parallel or competitive shift (3.16 X 10(-8) and 10(-7) mol/l) as well as a nonparallel or unsurmountable shift (3.16 X 10(-7) and 10(-6) mol/l) of the histamine dose response curves. Using the dose ratio test, it was concluded that terfenadine competes at the same receptors as chlorpheniramine, namely, the histamine H1-receptors. The antihistaminic effects of terfenadine, both the competitive and unsurmountable effects, were difficult to reverse by washout techniques whereas the nonspecific effects (against acetylcholine and barium chloride) could be readily washed out. The unsurmountable antagonism of histamine by terfenadine may result from a slow dissociation of terfenadine from the histamine H1-receptor. When terfenadine (2 mg/kg) or chlorpheniramine (2 mg/kg) was administered systemically, either orally or intraperitoneally, to guinea pigs and the antihistaminic effect assessed in vitro (isolated ileal strips and tracheal strips) terfenadine consistently produced a longer duration of action than chlorpheniramine. It is concluded that terfenadine is a potent, selective histamine H1-receptor antagonist; the kinetics of association/dissociation of terfenadine with histamine H1-receptors may account for the long-lasting antihistaminic effect in various animal models.