Four non-sedating antihistamines (astemizole, cetirizine, loratadine and terfenadine) were investigated for in vitro and ex vivo binding to histamine-H1 receptors in guinea-pig cerebellum and lung. In vitro, all the drugs dissociated slowly from H1 receptors (half-times greater than or equal to 100 min), Ki,app-values decreased with longer incubation times for potent lipophylic agents (astemizole and terfenadine) Ki,app-values were lower with more dilute tissue suspensions. In optimized assay conditions astemizole showed a Ki,app-value of 0.2 microM. Terfenadine, cetirizine and loratadine bound with 30-, 80- and 100-times lower affinity to H1 receptors. The occupancy of lung and cerebellar H1 receptors was investigated after oral administration of various dosages of the drugs and at several times after drug administration, using ex vivo binding techniques. Astemizole was a very potent compound showing complete differentiation between lung and cerebellar receptor occupation (with 0.63 mg/kg: 70% of lung H1 receptors were occupied, with less than 10% of cerebellar H1 receptor occupancy). A 7-times higher dose of terfenadine was required to induce the same effect. Astemizole produced a rapid and complete occupancy of lung receptors, which was maintained up to 72 h after administration. In contrast, terfenadine produced a peak effect at 1 h and was completely eliminated from lung receptors in 24 h. Loratadine and cetirizine only poorly differentiated between lung and cerebellar receptor occupancy (at 2.5 mg/kg: 70 and 60% of lung receptor occupancy, 50 and 70% of cerebellar receptor occupancy).(ABSTRACT TRUNCATED AT 250 WORDS)