Ullrich K J, Rumrich G, Klöss S
Max-Planck-Institut für Biophysik, Frankfurt/Main, Federal Republic of Germany.
Kidney Int. 1989 Jul;36(1):78-88. doi: 10.1038/ki.1989.164.
In order to study the interaction of sulfamoyl- and phenoxy diuretics as well as of beta-lactam antibiotics with the contraluminal anion and cation transport systems the inhibitory potency of these substances against the influx of 3H-para-aminohippurate, 14C-succinate, 35S-sulfate and 3H-N1-methylnicotinamide into cortical tubular cells have been determined. 1.) 2-, 3- and 4-sulfamoylbenzoate inhibit contraluminal PAH influx. N-dipropyl substitution to yield probenecid or ring-substitution to yield furosemide and piretanide augment the inhibitory potency. However, hydrochlorothiazide and acetazolamide exert only a moderate inhibitory potency. Succinate transport was inhibited by furosemide only. Sulfate transport was inhibited by furosemide and 3-sulfamoyl-4-phenoxybenzoate as well as by probenecid, piretanide, hydrochlorothiazide and acetazolamide. 2.) Phenoxyacetate, -propionate, and -butyrate exert increasing inhibition against PAH transport. The weed-killers 2,4-dichloro-, and 2,4,5-trichlorophenoxyacetate (2,4 D and 2,4,5 T) had a similar inhibitory potency, while ethacrynic acid showed a lower and the uricosuric tienilic acid a higher inhibitory potency. None of the compounds of this group interact with contraluminal succinate transport, and only the multiring-substituted compounds 2,4 D, 2,4,5 T, ethacrynic and tienilic acid interact slightly with the sulfate transporter. 3.) The monocarboxylic penicillins benzylpenicillin and phenoxymethylpenicillin as well as the dicarboxylic ticarcillin interact with the contraluminal PAH transport. The aminopenicillin ampicillin had a lower, and apalcillin a higher inhibitory potency than monocarboxylic penicillin. Benzylpenicillin showed small inhibition against succinate transport and ticarcillin against sulfate transport. 4.) The monocarboxylic cephalosporine, 6315 S Shionogi, and the aminocephalosporines, cephalexin and cefadroxil, showed an app. Ki.PAH as the comparable penicillins. The zwitterions cephaloridine and cefpirome did not interact with the PAH transporter, but with the organic cation (NMN) transporter. Amongst the amino-thiazol-containing compounds cefotaxime, ceftriaxone, and cefodizime, increasing interaction with the PAH transporter was seen dependent of a second ionizable anionic group. Compounds with two ionizable anionic groups (cefsulodin, ceftriaxone, cefodizime) exert also a small inhibitory potency against sulfate transport. None of the cephalosporins interacted with the dicarboxylate transporter. The interaction pattern of the tested compounds is in accordance with the specificity requirements for the contraluminal transporters depending on electrical charge and hydrophobicity.
为了研究氨磺酰类和苯氧基类利尿剂以及β-内酰胺类抗生素与管腔对侧阴离子和阳离子转运系统的相互作用，已测定了这些物质对3H-对氨基马尿酸、14C-琥珀酸盐、35S-硫酸盐和3H-N1-甲基烟酰胺流入皮质肾小管细胞的抑制效力。1.）2-、3-和4-氨磺酰苯甲酸抑制管腔对侧PAH的流入。N-二丙基取代生成丙磺舒或环取代生成呋塞米和吡咯他尼可增强抑制效力。然而，氢氯噻嗪和乙酰唑胺仅具有中等抑制效力。琥珀酸盐转运仅被呋塞米抑制。硫酸盐转运被呋塞米、3-氨磺酰-4-苯氧基苯甲酸以及丙磺舒、吡咯他尼、氢氯噻嗪和乙酰唑胺抑制。2.）苯氧乙酸、苯氧丙酸和苯氧丁酸对PAH转运的抑制作用增强。除草剂2,4-二氯苯氧乙酸和2,4,5-三氯苯氧乙酸（2,4-D和2,4,5-T）具有相似的抑制效力，而依他尼酸的抑制效力较低，促尿酸尿的替尼酸的抑制效力较高。该组中的化合物均不与管腔对侧琥珀酸盐转运相互作用，只有多环取代的化合物2,4-D、2,4,5-T、依他尼酸和替尼酸与硫酸盐转运体有轻微相互作用。3.）单羧基青霉素苄青霉素和苯氧甲基青霉素以及二羧基替卡西林与管腔对侧PAH转运相互作用。氨基青霉素氨苄西林的抑制效力低于单羧基青霉素，阿帕西林的抑制效力高于单羧基青霉素。苄青霉素对琥珀酸盐转运有轻微抑制作用，替卡西林对硫酸盐转运有抑制作用。4.）单羧基头孢菌素6315 S盐野义以及氨基头孢菌素头孢氨苄和头孢羟氨苄显示出与相应青霉素相当的PAH的表观Ki值。两性离子头孢噻啶和头孢匹罗不与PAH转运体相互作用，但与有机阳离子（NMN）转运体相互作用。在含氨基噻唑的化合物头孢噻肟、头孢曲松和头孢地嗪中，观察到与PAH转运体的相互作用增加，这取决于第二个可电离的阴离子基团。具有两个可电离阴离子基团的化合物（头孢磺啶、头孢曲松、头孢地嗪）对硫酸盐转运也有轻微抑制效力。没有一种头孢菌素与二羧酸盐转运体相互作用。所测试化合物的相互作用模式符合管腔对侧转运体对电荷和疏水性的特异性要求。
