SL-910102

A reliable and sensitive radioreceptor assay based on rat lung homogenate as receptor preparation was developed to determine the angiotensin-II antagonistic profile of losartan and its main active metabolite EXP 3174 as well as its congeners exemplified by UP 269-6 and SL 91.0102-90 DL.This method proved to be precise with an intra- and interday variability of less than 10% and a limit of quantification ≤ 1 ng ml^-1.The anal. of the K_i values in protein-free Hepes-buffer vs. blank human or rat plasma revealed the distinct high plasma-protein binding of EXP 3174 which consequently caused a dramatic drop of potency from 10-15-fold in the buffer to only about 2-fold in control plasma, when compared to the parent compound losartan and the two congeners investigated.Upon evaluation of clin. samples by both the reported radioreceptor assay (RRA) and the established high-performance liquid chromatog. (HPLC), the correlation of the normalized data pairs (concentration equivalent) suggested the contribution of active metabolites to the angiotensin-II antagonistic effect of SL 91.0102-90 DL, but not to the effect of UP 269-6.In the context of an extended preclin. study in rats, the correlation of RRA with the resp. HPLC concentration equivalent of losartan and its main active metabolite EXP 3174 confirmed previous findings that only losartan and EXP 3174 exert the angiotensin-II-AT₁ receptor blockade without the contribution of other metabolites.