Ueda H, Horibe Y, Kim K J, Lee V H
Department of Pharmaceutical Sciences, University of Southern California, Los Angeles 90089-9121, USA.
Invest Ophthalmol Vis Sci. 2000 Mar;41(3):870-6.
To characterize carrier-mediated organic cation drug transport in the rabbit conjunctiva.
The transport of [14C]guanidine, the model substrate, in the excised pigmented rabbit conjunctiva was evaluated in the modified Ussing chamber. Tetraethylammonium (TEA) transport also was investigated to determine substrate specificity.
The apparent permeability coefficient for guanidine and TEA in the mucosal-to-serosal (ms) direction was 5.4 and 49.6 times greater than that in the serosal-to-mucosal (sm) direction, respectively. Guanidine transport in the ms (but not sm) direction revealed temperature and concentration dependency over 0.02 to 10 mM with an apparent Michaelis-Menten constant of 3.1 mM and a maximal flux of 11.4 nmol/(cm2 x h). Net guanidine transport measured at 0.1 mM across the conjunctiva was decreased by 71% or 82%, respectively, on the addition of 1 microM valinomycin (a K+ ionophore) in both bathing fluids or in a high K+ buffer in the mucosal fluid. Interestingly, net guanidine transport was reduced, rather than enhanced, by 63% upon acidifying the mucosal bathing fluid. By contrast, net guanidine transport was not affected by the serosal presence of 0.5 mM ouabain (a Na+, K+-ATPase inhibitor), by the mucosal and serosal presence of 0.1 microM monensin (a Na+ ionophore) or 0.3 microM carbonyl cyanide p-(trifluoromethoxy)phenyl-hydrazone (FCCP, a H+ ionophore). Guanidine transport in the ms direction was polyspecific, as indicated by the 48% to 82% inhibition by structurally diverse amines. In particular, guanidine ms transport was inhibited by the antiglaucoma drugs dipivefrine (72%), brimonidine (70%), and carbachol (78%).
A carrier-mediated organic cation transport process appears to exist in the conjunctiva, mediating the absorption of organic amines, including certain amine-type ophthalmic drugs. This process may be driven by an inside-negative apical membrane potential difference.
表征家兔结膜中载体介导的有机阳离子药物转运。
在改良的Ussing室中评估模型底物[¹⁴C]胍在家兔离体色素结膜中的转运。还研究了四乙铵（TEA）的转运以确定底物特异性。
胍和TEA在黏膜到浆膜（ms）方向的表观渗透系数分别比在浆膜到黏膜（sm）方向大5.4倍和49.6倍。胍在ms（而非sm）方向的转运在0.02至10 mM范围内呈现温度和浓度依赖性，表观米氏常数为3.1 mM，最大通量为11.4 nmol/(cm²·h)。在两侧浴液中或黏膜液中的高钾缓冲液中加入1 μM缬氨霉素（一种钾离子载体）后，在0.1 mM浓度下测量的胍跨结膜的净转运分别降低了71%或82%。有趣的是，酸化黏膜浴液后，胍的净转运降低了63%，而非增加。相比之下，浆膜侧存在0.5 mM哇巴因（一种钠钾ATP酶抑制剂）、黏膜和浆膜侧存在0.1 μM莫能菌素（一种钠离子载体）或0.3 μM羰基氰对（三氟甲氧基）苯基腙（FCCP，一种氢离子载体）对胍的净转运没有影响。ms方向的胍转运具有多特异性，不同结构的胺类可抑制48%至82%。特别是，胍的ms转运受到抗青光眼药物地匹福林（72%）、溴莫尼定（70%）和卡巴胆碱（78%）的抑制。
结膜中似乎存在载体介导的有机阳离子转运过程，介导包括某些胺类眼科药物在内的有机胺的吸收。该过程可能由顶端膜内侧负电位差驱动。
