MECHANISTIC EVALUATION OF MODIFICATIONS OF DISTRIBUTION PHARMACOKINETIC PARAMETERS OF MODEL ORGANIC ANIONS IN PRESENCE OF A MODEL RENAL TUBULAR SECRETION INHIBITOR IN RATS
MECHANISTIC EVALUATION OF MODIFICATIONS OF DISTRIBUTION PHARMACOKINETIC PARAMETERS OF MODEL ORGANIC ANIONS IN PRESENCE OF A MODEL RENAL TUBULAR SECRETION INHIBITOR IN RATS
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DOI：
10.1002/jps.2600641113
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发表时间：
1975-01-01
影响因子：
3.8
通讯作者：
NAGWEKAR, JB
中科院分区：
文献类型：
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作者：
AMIN, YM;NAGWEKAR, JB
研究了DL-tropic acid （VIII）对模型化合物苯甲酰甲酸(I)、对甲基苯甲酰甲酸（II）、对乙基苯甲酰甲酸（III）、D-(-)-扁桃酸（IV）、D-(-)-对甲基扁桃酸(V)、D-(-)-对乙基扁桃酸（VI）和D-(-)-对异丙基扁桃酸（VII）在大鼠体内分布的药动学参数的影响。由于VIII是肾小管分泌I-VII的竞争性抑制剂，并且由于所有这些化合物（I-VIII）与血浆蛋白的结合可以忽略不计，既不被肾小管代谢也不被肾小管重吸收，因此它们被认为是模型化合物。因此，观察到的I-VII分布药代动力学参数值的变化归因于VIII对化合物在大鼠体间跨膜转运的影响。I， IV和VII的中央室的表观体积减少，IV-VII的周围室的表观体积增加，其他化合物的中央或周围室的体积没有变化，化合物从一个隔室转移到另一个隔室的速率常数比值的增加可以用化合物阴离子跨膜运输的“水孔”机制和组织膜的异孔性来解释。
The effects of DL-tropic acid (VIII) on the distribution pharmacokinetic parameters of the model compounds benzoylformic acid (I),p-methylbenzoylformic acid (II),p-ethylbenzoylformic acid (III),D-(–)-mandelic acid (IV),D-(–)-p-methylmandelic acid (V),D-(–)-p-ethylmandelic acid (VI), andD-(–)-p-isopropylmandelic acid (VII) were studied in rats. Since VIII is a competitive inhibitor of renal tubular secretion of I-VII and since all of these compounds (I-VIII) are negligibly bound to plasma proteins and are neither metabolized nor reabsorbed from the renal tubules, they were considered as model compounds. Therefore, changes observed in the values of the distribution pharmacokinetic parameters of I-VII were attributed to the influence of VIII on the transmembrane transport of the compounds between body compartments in rats. The decrease in the apparent volumes of the central compartments for I, IV, and VII, the increase in the apparent volumes of the peripheral compartments for IV-VII, the absence of change in the volumes of the central or peripheral compartments for the other compounds, and the increase in the ratios of the rate constants of the transfer of compounds from one compartment into another for I and IV-VII were explained in terms of the “aqueous pore” mechanism for the transmembrane transport of the anions of the compounds as well as the heteroporosity of the tissue membranes.