眼科用β受体阻滞剂：多次给药后通过放射受体分析法测定血浆和房水浓度

Phan T M, Nguyen K P, Giacomini J C, Lee D A

Jules Stein Eye Institute, UCLA School of Medicine.

J Ocul Pharmacol. 1991 Fall;7(3):243-52.

We determined the binding affinities of multiple doses of four ophthalmic beta-blockers, timolol, betaxolol, levobunolol and carteolol, to the beta-1 and beta-2 receptors. With a Ki value of 0.39 nM and 0.36 nM for the beta-1 and beta-2 receptors, respectively, levobunolol shows the highest binding affinity to both beta receptors. The Ki values of timolol (1.97 nM for the beta-1 receptor and 2.0 nM for the beta-2 receptor) and of carteolol (0.83 nM and 0.85 nM for the beta-1 and beta-2 receptors, respectively) are characteristic of a nonspecific beta-blocker. On the contrary, betaxolol is a beta-1 specific antagonist (Ki of 23.33 nM) and has a very low binding affinity to the beta-2 receptor (Ki of 200.00 nM). With a radioreceptor assay, levels of beta-antagonist were measured in the plasma and aqueous humor 1 hour and 12 hours after instillation of 50 microliters of 0.5% or 2% each of the four beta-blockers into the rabbit eye. At 1 hour after administration, the plasma levels of timolol, levobunolol, and carteolol are 9.89 ng/ml, 1.60 ng/ml and 8.00 ng/ml, respectively; such levels of 11.82 to 29.22 times the respective Ki values cause a virtually total blockade of both beta-1 and beta-2 receptors and suggest significant systemic absorption. Betaxolol has a peak 1 hour plasma level of 22.28 ng/ml, which is equivalent to only 3.08 times its Ki for the beta-1 receptor and 0.36 times its Ki for the beta-2 receptor; it has less systemic beta-1 blocking activity than the other three drugs and very minimal systemic beta-2 blocking activity. Peak aqueous humor concentrations of all 4 beta-blockers are extremely elevated at 1 hour after administration (timolol 1613.58 ng/ml; betaxolol 866.06 ng/ml; levobunolol 750.89 ng/ml; and carteolol 859.18 ng/ml). Such levels of 14 to 7192 times the respective Ki values should cause a virtually complete blockade of both beta-1 and beta-2 receptors in the iris-ciliary body complex. At 12 hours after administration, plasma levels of all four beta blockers remain moderately elevated (timolol 0.94 ng/ml; betaxolol 9.43 ng/ml; levobunolol 0.66 ng/ml; and carteolol 1.61 ng/ml). Trough aqueous humor levels of levobunolol (43.38 ng/ml) and carteolol (92.81 ng/ml) remain elevated at least 300 times their Ki value. On the contrary, 12-hour trough aqueous humor levels of timolol (33.67 ng/ml) and betaxolol (94.86 ng/ml) have decreased to 2 to 40 times their Ki value, which may explain their requirement for twice daily administration clinically.

我们测定了四种眼科β受体阻滞剂（噻吗洛尔、倍他洛尔、左布诺洛尔和卡替洛尔）多剂量对β1和β2受体的结合亲和力。左布诺洛尔对β1和β2受体的Ki值分别为0.39 nM和0.36 nM，显示出对两种β受体的最高结合亲和力。噻吗洛尔（β1受体的Ki值为1.97 nM，β2受体的Ki值为2.0 nM）和卡替洛尔（β1受体的Ki值为0.83 nM，β2受体的Ki值为0.85 nM）的Ki值具有非特异性β受体阻滞剂的特征。相反，倍他洛尔是一种β1特异性拮抗剂（Ki为23.33 nM），对β2受体的结合亲和力非常低（Ki为200.00 nM）。通过放射受体测定法，在将50微升0.5%或2%的四种β受体阻滞剂分别滴入兔眼后1小时和12小时，测量血浆和房水中β拮抗剂的水平。给药后1小时，噻吗洛尔、左布诺洛尔和卡替洛尔的血浆水平分别为9.89 ng/ml、1.60 ng/ml和8.00 ng/ml；这些水平分别是各自Ki值的11.82至29.22倍，几乎完全阻断了β1和β2受体，表明有显著的全身吸收。倍他洛尔1小时血浆峰值水平为22.28 ng/ml，仅相当于其对β1受体Ki值的3.08倍，对β2受体Ki值的0.36倍；其全身β1阻断活性低于其他三种药物，全身β2阻断活性非常小。所有4种β受体阻滞剂给药后1小时房水峰值浓度极高（噻吗洛尔1613.58 ng/ml；倍他洛尔866.06 ng/ml；左布诺洛尔750.89 ng/ml；卡替洛尔859.18 ng/ml）。这些水平分别是各自Ki值的14至7192倍，应能几乎完全阻断虹膜睫状体复合体中的β1和β2受体。给药后12小时，所有四种β受体阻滞剂的血浆水平仍中度升高（噻吗洛尔0.94 ng/ml；倍他洛尔9.43 ng/ml；左布诺洛尔0.66 ng/ml；卡替洛尔1.61 ng/ml）。左布诺洛尔（43.38 ng/ml）和卡替洛尔（92.81 ng/ml）的房水谷值水平至少比其Ki值高300倍。相反，噻吗洛尔（33.67 ng/ml）和倍他洛尔（94.86 ng/ml）12小时房水谷值水平已降至其Ki值的2至40倍，这可能解释了它们临床上需要每日给药两次的原因。