Quantitative relationship between structure and peritoneal membrane transport based on physiological pharmacokinetic concepts for acidic drugs.
Quantitative relationship between structure and peritoneal membrane transport based on physiological pharmacokinetic concepts for acidic drugs.
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基于酸性药物的生理药代动力学概念的结构与腹膜转运之间的定量关系。
DOI：
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发表时间：
1995
期刊：
影响因子：
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通讯作者：
F. Ichimura
中科院分区：
文献类型：
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作者：
E. Nakashima;R. Matsushita;T. Ohshima;A. Tsuji;F. Ichimura
为了定量描述药物的腹膜转运，应用动力学模型，该模型涉及透析液的体积和渗透压的变化以及药物穿过腹膜的扩散和对流。在酸性药物中，估计大鼠中未结合药物的表观腹膜渗透性（Pd）和辛醇：水系统（pH 7.4）中的分配系数（Papp）。使用未结合分数（fS）的值，根据腹膜内给药后血清和腹膜透析液中的浓度-时间曲线估计药物的Pd值。基于生理药代动力学模型计算固有膜渗透性（Pdm）。硫喷妥钠和硫戊巴比妥钠的fS.Pdm值（6.5和5.4ml/min）是有效腹膜血流量的2-3倍，表明高亲脂性巴比妥类药物的腹膜转运主要受血流量限制。有证据表明log Pdm和log Papp之间存在高度相关性。考虑到这些关系，我们估计了喹诺酮羧酸的Pdm。喹诺酮类药物的fS.Pdm值小于腹膜有效血流量的10%，表明喹诺酮类药物的腹膜转运主要是受扩散限制的，这是因为其亲脂性较低。总之，log Pdm和log Papp之间具有良好的相关性。Pdm的预测可用于描述腹膜药代动力学。
To describe quantitatively the peritoneal transport of drugs, the kinetic model, which involves changes in the volume and osmolality of the dialysate as well as the diffusion and convection of drugs across the peritoneum, was applied. The apparent peritoneal permeability (Pd) of unbound drugs in rats and the partition coefficient (Papp) in an octanol:water system at pH 7.4 were estimated among acidic drugs. Using the values of unbound fraction (fS), the Pd values of the drugs were estimated from concentration-time profiles in serum and the peritoneal dialysate after intraperitoneal administration of drugs. The intrinsic membrane permeability (Pdm) was calculated based on a physiological pharmacokinetic model. The fS.Pdm values of thiopental and thiamylal (6.5 and 5.4 ml/min) were 2-3 times greater than the effective peritoneal blood flow, indicating that the peritoneal transport of the barbiturates with high lipophilicity was dominantly blood flow-limited. Evidence shows a high degree of correlation between log Pdm and log Papp. By considering the relationships, we estimated the Pdm of quinolonecarboxilic acids. The fS.Pdm values of quinolonecarboxilic acids were < 10% of the peritoneal effective blood flow rate, indicating that the peritoneal transport of quinolonecarboxilic acids was dominantly diffusion-limited because of low lipophilicity. In conclusion, there was a good correlation between log Pdm and log Papp. The prediction of Pdm can be useful to describe the peritoneal pharmacokinetics.