Influence of ion gradients on the transbilayer distribution of dibucaine in large unilamellar vesicles.
Influence of ion gradients on the transbilayer distribution of dibucaine in large unilamellar vesicles.
复制标题
离子梯度对大单层囊泡中地布卡因跨双层分布的影响。
作者：
L. Mayer;K. Wong;K. Menon;C. Chong;P. Harrigan;P. Cullis
研究了大单层囊泡摄取地布卡因对质子梯度(pH增量；内层酸性)或膜电位(psi内层负值)的响应。地布卡因的摄取响应于增量pH，以与药物的中性(去质子化)形式的渗透一致的方式快速进行，达到Henderson-Hasselbach平衡，其中[地布卡因]In/[地布卡因]Out=[H+]In/[H+]Out，其中累积的药物的绝对量对内部环境的缓冲能力敏感。在适当的条件下，药物的绝对体内浓度高(约120 mM)，结合高的捕集效率(超过90%)。地布卡因摄取对德尔塔psi的反应要慢一个数量级以上，并且不能直接归因于对德尔塔psi诱导的德尔塔pH的摄取。这种诱导的增量pH太小(小于或等于1.5个pH单位)，不能解释所实现的跨膜地布卡因浓度梯度，并且不能与增量psi达到电化学平衡。通过使用永久带正电的地布卡因类似物(N-甲基地布卡因)，获得了支持带电(质子化)形式的地布卡因响应于psi的可能性的结果。此外，结果表明，依赖于psi的摄取可能依赖于药物在囊泡内部的沉淀物的形成。地布卡因对离子梯度的响应被囊泡吸收，在药物输送和控释应用中具有直接作用，并与体内细胞和细胞器对药物的封存过程有关。
The uptake of dibucaine into large unilamellar vesicles in response to proton gradients (delta pH; inside acidic) or membrane potentials (delta psi; inside negative) has been investigated. Dibucaine uptake in response to delta pH proceeds rapidly in a manner consistent with permeation of the neutral (deprotonated) form of the drug, reaching a Henderson-Hasselbach equilibrium where [dibucaine]in/[dibucaine]out = [H+]in/[H+]out and where the absolute amount of drug accumulated is sensitive to the buffering capacity of the interior environment. Under appropriate conditions, high absolute interior concentrations of the drug can be achieved (approximately 120 mM) in combination with high trapping efficiencies (in excess of 90%). Dibucaine uptake in response to delta psi proceeds more than an order of magnitude more slowly and cannot be directly attributed to uptake in response to the delta pH induced by delta psi. This induced delta pH is too small (less than or equal to 1.5 pH units) to account for the transmembrane dibucaine concentration gradients achieved and does not come to electrochemical equilibrium with delta psi. Results supporting the possibility that the charged (protonated) form of dibucaine can be accumulated in response to delta psi were obtained by employing a permanently positively charged dibucaine analogue (N-methyldibucaine). Further, the results suggest that delta psi-dependent uptake may depend on formation of a precipitate of the drug in the vesicle interior. The uptake of dibucaine into vesicles in response to ion gradients is of direct utility in drug delivery and controlled release applications and is related to processes of drug sequestration by cells and organelles in vivo.
DOI：
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发表时间：
1983
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Garlid,KD;Nakashima,RA
通讯作者：
Nakashima,RA
脂质体中电压依赖性质子通量。
DOI：
10.1016/0005-2728(84)90222-6
发表时间：
1984
期刊：
Biochimica et biophysica acta
影响因子：
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作者：
Garcia,ML;Kitada,M;Eisenstein,HC;Krulwich,TA
通讯作者：
Krulwich,TA