UTILIZATION OF MODEL COMPOUNDS TO EVALUATE EFFECTS OF SLIGHT CHEMICAL MODIFICATIONS ON THEIR DISTRIBUTION PHARMACOKINETIC PARAMETERS IN RATS AND MECHANISMS INFERRED FOR THEIR TRANSMEMBRANE TRANSPORT
UTILIZATION OF MODEL COMPOUNDS TO EVALUATE EFFECTS OF SLIGHT CHEMICAL MODIFICATIONS ON THEIR DISTRIBUTION PHARMACOKINETIC PARAMETERS IN RATS AND MECHANISMS INFERRED FOR THEIR TRANSMEMBRANE TRANSPORT
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DOI：
10.1002/jps.2600641112
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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：
--
作者：
AMIN, YM;NAGWEKAR, JB
在大鼠中研究了模型化合物苯甲酰基甲酸（I）、对甲基苯甲酰基甲酸（II）、对乙基苯甲酰基甲酸（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）的药代动力学，以确定化合物的轻微化学修饰对其在大鼠中分布药代动力学参数的影响。所考虑的特定化学修饰的影响是IV的>CHOH基团对I的>C = O基团的影响，I和IV的对位烷基化作用，以及IV同系物的支链烷基（异丙基）对直链烷基的影响。虽然I从血液中的消失可通过三室开放模型描述，但IV的消失可通过二室开放模型描述。IV的中央室表观分布容积（V1）小于I，但IV的外周室表观分布容积（V2）大于I的外周室表观分布容积（V2+V3）。血液中V、VI和VII的消失也可通过二室开放模型描述，但这些化合物的表观V1和V2低于母体化合物IV。然而，II和III从血液中消失可通过一室开放模型描述。适当的分布药代动力学参数的评价表明，这些化合物的阴离子的外周室由适度灌注的组织组成，并且这些有机阴离子在中央和外周室之间的跨膜转运主要通过扩散通过水性膜孔发生，所述水性膜孔内衬有膜蛋白和/或磷脂的极性部分。这些化合物的烷基基团与膜孔的蛋白质和/或磷脂的疏水基团之间可能增加的疏水键合涉及减少对位烷基化同系物在外周隔室中的分布，从而减少其外周隔室的体积。中央室的组织的膜的不均匀孔隙率被提出为与IV或VII相比，V和VI的中央室的体积减小的原因。
The pharmacokinetics of each 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 to determine the influence of slight chemical modifications of the compounds on their distribution pharmacokinetic parameters in rats. The effects of the specific chemical modifications considered were those of the >CHOH group of IV against the >CO group of I, thepara‐alkylation of I and IV, and the branched alkyl group (isopropyl) against the straight chain alkyl groups of the homologs of IV. While the disappearance of I from the blood was describable by the three‐compartment open model, that of IV was describable by the two‐compartment open model. The apparent volume of distribution of the central compartment (V1) for IV was smaller than that for I, but the volume of the peripheral compartment (V2) for IV was greater than that (V2+V3) for I. The disappearance of V, VI, and VII from the blood was also describable by the two‐compartment open model, but the apparentV1andV2for these compounds were lower than those for the parent compound, IV. However, the disappearance of II and III from the blood was describable by a one‐compartment open model. Evaluation of the appropriate distribution pharmacokinetic parameters suggested that the peripheral compartment for the anions of these compounds consisted of moderately perfused tissues and that the transmembrane transport of these organic anions between the central and peripheral compartments occurs by diffusion mainly through the aqueous membrane pores, which are lined with polar portions of the membrane proteins and/or phospholipids. The possible increased hydrophobic bonding between the alkyl groups of these compounds and the hydrophobic groups of the proteins and/or phospholipids of the membrane pores is implicated to decrease the distribution of thepara‐alkylated homologs into the peripheral compartments and, consequently, diminish the volumes of their peripheral compartments. The heteroporosity of the membranes of the tissues of the central compartment is proposed as the reason for the diminished volume of the central compartment for V and VI as compared to that of IV or VII.