Metabolic disposition of terfenadine in laboratory animals

Alpha-[4-(1,1-Dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-1- piperidinebutanol (terfenadine, RMI 9918, Triludan, Teldane, resp.), a clinically effective antihistamine, with little or no central nervous system effects, was investigated in order to understand its metabolic disposition. These 14C-terfenadine studies were performed in laboratory animals, principally the rat, and also in beagle dog and monkey (Macaca mulatta). In all three species the fecal pathway of excretion was predominant with nearly all the elimination occurring within 24 h of administration. The data suggest that biliary excretion plays a prominent role. Tissue distribution studies indicated that the liver and lung, relative to other tissues, exhibited the highest concentrations of 14C-terfenadine equivalents. However, brain had low amounts of 14C-terfenadine which was in general agreement with the whole-body autoradiographic studies which did not show radioactivity in brain or spinal cord. The evidence suggests that terfenadine was metabolized rapidly with no terfenadine in urine or bile and small amounts in feces. Tissue concentrations of terfenadine were in the low nanogram range and peaked at 0.5-1.0 h with lung exhibiting the greatest and the brain sub-quantifiable amounts. The ratios of 14C-terfenadine eq/terfenadine were high and greatest in the liver and kidney. These studies demonstrated that terfenadine was readily absorbed and eliminated, virtually had undergone complete biotransformation and exhibited very low tissue concentrations per se.