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.