Convective washout reduces the antidiarrheal efficacy of enterocyte surface-targeted antisecretory drugs
Convective washout reduces the antidiarrheal efficacy of enterocyte surface-targeted antisecretory drugs
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DOI：
10.1085/jgp.201210885
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发表时间：
2013-02-01
影响因子：
3.8
通讯作者：
Verkman, A. S.
中科院分区：
文献类型：
--
作者：
Jin, Byung-Ju;Thiagarajah, Jay R.;Verkman, A. S.
霍乱等分泌性霍乱是发展中国家发病率和死亡率的主要原因。我们以前介绍了抗分泌治疗腹泻的概念，使用氯离子通道抑制剂靶向囊性纤维化跨膜传导调节通道孔的细胞外表面的肠上皮细胞。然而，这种策略的一个问题是，快速的液体分泌可能导致对流药物洗脱，这将限制细胞外靶向抑制剂的疗效。在这里，我们开发了一个对流扩散模型的冲洗在解剖学上准确的三维模型，包括圆柱形的隐窝和绒毛分泌液体到一个中央管腔的人肠。输入参数包括初始管腔流量和抑制剂浓度、抑制剂解离常数（K-d）、隐窝/绒毛分泌和抑制剂扩散。我们模拟了膜不渗透和渗透性抑制剂。该模型预测，如霍乱中发生的高隐窝流体分泌的抑制剂效力大大降低。我们的结论是，口服给药的膜不渗透的表面靶向抑制剂的抗分泌功效需要（a）高抑制剂亲和力（低纳摩尔Kd）以获得足够高的管腔抑制剂浓度（>100倍Kd），和（B）与口服给药频率相比持续的高管腔抑制剂浓度或缓慢的抑制剂解离。从血液递送的表面靶向可渗透抑制剂的功效需要高的抑制剂渗透性和血液浓度（相对于K-d）。
Secretory diarrheas such as cholera are a major cause of morbidity and mortality in developing countries. We previously introduced the concept of antisecretory therapy for diarrhea using chloride channel inhibitors targeting the cystic fibrosis transmembrane conductance regulator channel pore on the extracellular surface of enterocytes. However, a concern with this strategy is that rapid fluid secretion could cause convective drug washout that would limit the efficacy of extracellularly targeted inhibitors. Here, we developed a convection-diffusion model of washout in an anatomically accurate three-dimensional model of human intestine comprising cylindrical crypts and villi secreting fluid into a central lumen. Input parameters included initial lumen flow and inhibitor concentration, inhibitor dissociation constant (K-d), crypt/villus secretion, and inhibitor diffusion. We modeled both membrane-impermeant and permeable inhibitors. The model predicted greatly reduced inhibitor efficacy for high crypt fluid secretion as occurs in cholera. We conclude that the antisecretory efficacy of an orally administered membrane-impermeant, surface-targeted inhibitor requires both (a) high inhibitor affinity (low nanomolar K-d) to obtain sufficiently high luminal inhibitor concentration (>100-fold K-d), and (b) sustained high luminal inhibitor concentration or slow inhibitor dissociation compared with oral administration frequency. Efficacy of a surface-targeted permeable inhibitor delivered from the blood requires high inhibitor permeability and blood concentration (relative to K-d).