薬物のヒト赤血球膜透過性へのHuman Serum Albuminの影響

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The binding properties to human serum albumin (HSA) and the transport of drugs through human erythrocyte membranes were examined with benzoic acid or its twenty-five derivatives (o-, m-, or p-hydroxybenzoic acid, o-, m-, or p-aminobenzoic acid, o-, m-, or p-nitrobenzoic acid, o-, m-, or p-toluic acid, o-, m-, or p-fluorobenzoic acid, o-, m-, or p-chlorobenzoic acid, o-, m-, or p-bromobenzoic acid, aspirin, salicyluric acid, α-resorcylic acid and γ-resorcylic acid) and with glycosides (arbutin, salicin, glycyrrhizin and four p-nitrophenylglycosides) or their aglycons (hydroquinone, saligenin, glycyrretinic acid and p-nitrophyenol). The drugs having hydroxyl group and amino group to o-site and those having nitro group, methyl group and halogen group to m- or p-site showed higher affinity with HSA and the plasma hindered the permeability of these drugs. The glycosides bind to each site (1,2,and 3) of HSA more weakly than do their aglycons and they were difficult for plasma to hinder membrane permeation. The binding constants of each drug to HSA (K_<b-site 1>, K_<b-site 2>, K_<b-site 3> and K_<b-total>) and the inhibition ratio (IR) related to the partition coefficient (P) : K_<b-site 1> (M^<-1>)=2.1479×10^3・√<P>-5.2824・P+2.0985×10^3 (R=0.9371), K_<b-site 2> (M^<-1>)=4.3741×10^3・√<P>-15.2068・P+6.5660×10^3 (R=0.6788), K_<b-site 3> (M^<-1>)=2.2176×10^4・logP+1.2022×10^4 (R=0.5227), K_<b-total> (M^<-1>)=1.0214×10^4・√<P>-33.3721・P+1.6919×10^4 (R=0.7413), IR (%)=19.885・logP+17.916 (R=0.8605). IR obtained from predictive equations (IR=17.837・logP-13.286・logK_<b-site 1>+0.175・√<K_<b-site 2>+0.074・√<K_<b-site 3>+37.355,R=0.9642,F=71.4937^<***>, ^<***> ; p<0.001) by multiple regression analysis was compatible with experimental IR.
1996-08-25

薬物のヒト赤血球膜透過性へのHuman Serum Albuminの影響

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