BISUBSTRATES - SUBSTANCES THAT INTERACT WITH BOTH, RENAL CONTRALUMINAL ORGANIC ANION AND ORGANIC CATION-TRANSPORT SYSTEMS .2. ZWITTERIONIC SUBSTRATES - DIPEPTIDES, CEPHALOSPORINS, QUINOLONE-CARBOXYLATE GYRASE INHIBITORS AND PHOSPHAMIDE THIAZINE CARBOXYLATES - NONIONIZABLE SUBSTRATES - STEROID-HORMONES AND CYCLOPHOSPHAMIDES

Citation
Kj. Ullrich et al., BISUBSTRATES - SUBSTANCES THAT INTERACT WITH BOTH, RENAL CONTRALUMINAL ORGANIC ANION AND ORGANIC CATION-TRANSPORT SYSTEMS .2. ZWITTERIONIC SUBSTRATES - DIPEPTIDES, CEPHALOSPORINS, QUINOLONE-CARBOXYLATE GYRASE INHIBITORS AND PHOSPHAMIDE THIAZINE CARBOXYLATES - NONIONIZABLE SUBSTRATES - STEROID-HORMONES AND CYCLOPHOSPHAMIDES, Pflugers Archiv, 425(3-4), 1993, pp. 300-312
Citations number
37
Categorie Soggetti
Physiology
Journal title
ISSN journal
00316768
Volume
425
Issue
3-4
Year of publication
1993
Pages
300 - 312
Database
ISI
SICI code
0031-6768(1993)425:3-4<300:B-STIW>2.0.ZU;2-W
Abstract
In order to test what chemical structure is required for a substrate t o interact not only with the contraluminal organic anion (p-aminohippu rate, PAH) transporter, but also with the organic cation (N-1-methylni cotinamide, NMeN, or tetraethylammonium, TEA) transporter, the stop-fl ow peritubular capillary perfusion method was applied and app. K-i val ues were evaluated. Zwitterionic hydrophobic dipeptides not only inter act with PAH but also with NMeN transport although with lower inhibito ry potency (K-i,K-PAH = 0.2-2.4; K-i,K-NMeN 6-14 mmol/l). Amongst the zwitterionic cephalosporins, which all inhibit PAH transport, the amin o cephalosporin analogue cefadroxil was identified to interact also wi th NMeN transport (K-i,K-PAH = 3.0, K-i,K-NMen = 11.2 mmol/l). All zwi tterionic naphthyridine and oxochinoline gyrase inhibitors tested inhi bit NMeN transport with app. K-i,K-NMeN values between 1.2 mmol/l and 4.7 mmol/l; the naphthyridine analogues show a good inhibitory potency against PAH transport (K-i,K-PAH approximate to = 0.4 mmol/l), the pi perazine-containing quinolone analogues have a moderate inhibitory pot ency (K-i,K-PAH = 1.1-2.5 mmol/l) and the piperazine-containing pipemi dic acid did not inhibit PAH transport at all. Zwitterionic thiazolidi ne carboxylate phosphamides also interact with both transporters (app. K-i,K-PAH approximate to 3.0; app. K-i,K-NMeN approximate to 18.0 mmo l/l). The nonionizable oxo- and hydroxy-group-containing corticosteroi d hormones also interact with the two transporters. (a) An OH group in position 21 is necessary for interaction with the PAH transporter, bu t not for interaction with the TEA transporter. (b) Introduction of an OH group in position 17 alpha abolishes interaction with the TEA tran sporter, but has different effects with the PAH transporter. (c) Intro duction of an OH group in position 6 abolishes interaction with both, the PAH and the TEA transporter. (d) A change of the side-group in pos ition 11 of corticosterone from -OH to -H to = O enhances interaction with the PAH transporter but has no effect on the interaction with the TEA transporter. Nonionizable 4- or 5-androstene analogues inhibit bo th transporters with app. K-i between 0.16 mmol/l and 0.64 mmol/l, if the steroids are soluble in a concentration greater than 1 mmol/l. Non ionizable oxazaphosphorins with more than one chloroethyl group intera ct with the PAH transporter with app. K-i between 0.84 mmol/l and 4.9 mmol/l and with the NMeN transporter with app. K-2 between 3.2 mmol/l and 18.7 mmol/l. Thus a substrate interacts with both transporters if it is sufficiently hydrophobic, possesses acidic and/or electron-attra cting plus basic and/or electron-donating groups, or possesses several electron-attracting nonionizable groups (O, OH, Cl). A certain spatia l arrangement of the interacting groups seems to be necessary.