THE ANALYSIS OF PLASMA KINETICS AND BETA-RECEPTOR-BINDING AND BETA-RECEPTOR-BLOCKING ACTIVITY OF TIMOLOL FOLLOWING ITS SMALL INTRAVENOUS DOSE

Plasma kinetics and beta-receptor blocking and -binding activity of ti molol was studied in six healthy volunteers following its intravenous 0.25 mg dose. Timolol concentrations were measured using radioreceptor assay (RRA), blocking activity by comparing the dose ratios (DRs) of the infusion rates of isoprenaline required to increase heart rate by 25 bpm (I25) and binding activity by determining the extent to which t imolol occupied beta1-receptors of rabbit lung and beta2-receptors of rat recticulocytes in undiluted plasma samples. Timolol was eliminated from plasma with a mean half-life for the elimination phase of 2.6 ho urs. The dose antagonized potently isoprenaline-induced tachycardia at least for four hours. The effect was excellently correlated with the estimated beta2-receptor binding activity of timolol in the circulatin g plasma. In conclusion, the small intravenous timolol dose was elimin ated from plasma by a fashion, which was very similar to its eighty-fo ld higher oral doses reported earlier in the literature. The 0.25 mg d ose was of considerable systemic beta-receptor blocking and -binding a ctivity, that may help to explain its reported side-effects following ocular drug administration. The extent to which beta-blocking agents o ccupy rabbit lung beta1- and rat reticulocyte beta2-receptors in the c irculation appears to predict the intensity and selectivity of their b eta-blocking effects in healthy volunteers.