Kaila T, Karhuvaara S, Huupponen R, Iisalo E
Department of Clinical Pharmacology, University of Turku, Finland.
Int J Clin Pharmacol Ther Toxicol. 1993 Jul;31(7):351-7.
Plasma kinetics and beta-receptor blocking and -binding activity of timolol 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 timolol occupied beta 1-receptors of rabbit lung and beta 2-receptors of rat reticulocytes in undiluted plasma samples. Timolol was eliminated from plasma with a mean half-life for the elimination phase of 2.6 hours. The dose antagonized potently isoprenaline-induced tachycardia at least for four hours. The effect was excellently correlated with the estimated beta 2-receptor binding activity of timolol in the circulating plasma. In conclusion, the small intravenous timolol dose was eliminated from plasma by a fashion, which was very similar to its eighty-fold higher oral doses reported earlier in the literature. The 0.25 mg dose was of considerable systemic beta-receptor blocking and -binding activity, that may help to explain its reported side-effects following ocular drug administration. The extent to which beta-blocking agents occupy rabbit lung beta 1- and rat reticulocyte beta 2-receptors in the circulation appears to predict the intensity and selectivity of their beta-blocking effects in healthy volunteers.
在6名健康志愿者静脉注射0.25毫克噻吗洛尔后，对其血浆动力学以及β受体阻断和结合活性进行了研究。使用放射受体分析法（RRA）测定噻吗洛尔浓度，通过比较使心率增加25次/分钟（I25）所需的异丙肾上腺素输注速率的剂量比（DRs）来测定阻断活性，并通过确定噻吗洛尔在未稀释血浆样本中占据兔肺β1受体和大鼠网织红细胞β2受体的程度来测定结合活性。噻吗洛尔从血浆中消除，消除相的平均半衰期为2.6小时。该剂量对异丙肾上腺素诱导的心动过速具有至少4小时的强效拮抗作用。该效应与循环血浆中噻吗洛尔估计的β2受体结合活性高度相关。总之，静脉注射小剂量噻吗洛尔从血浆中的消除方式，与其文献中早期报道的高80倍的口服剂量非常相似。0.25毫克剂量具有相当大的全身β受体阻断和结合活性，这可能有助于解释其眼部给药后报道的副作用。β受体阻滞剂在循环中占据兔肺β1受体和大鼠网织红细胞β2受体的程度，似乎可以预测其在健康志愿者中β阻断作用的强度和选择性。
