EFFECT OF SUBSTITUTED BENZOYLGLYCINES (HIPPURATES) AND PHENYLACETYLGLYCINES ON P-AMINOHIPPURATE TRANSPORT DOG RENAL MEMBRANE-VESICLES

The effect of substituted benzoylglycines (hippurates) and phenylacety lglycines on the transport of p-aminohippurate (PAH) was studied in ba solateral (BLMV) and brush border membrane vesicles (BBMV) isolated fr om dog kidney cortex. The probenecid-sensitive part of 100 mu M [H-3]P AH uptake into BLMV and BBMV was measured in the presence and absence of 5 mM glycine conjugate. The benzoyl- and phenylacetylglycines studi ed were substituted in the 2-, 3-, or 4-position with an H, CH3, OCH3 or OH group. Benzoylglycines were stronger inhibitors of PAH transport than phenylacetylglycines and the inhibitory potency of the conjugate s was in general lower against the transporter in BBMV than BLMV. The specificities of the transporters in both membranes appear to be very similar. The inhibitory potency of the benzoylglycines, expressed as t he apparent inhibition constant (logK(i)), did not show a linear relat ionship with their lipophilicity as determined by reversed phase HPLC. Deviation from linearity was caused mainly by the 3-OH and 4-OH analo gs, which showed a greater inhibitory potency than expected from their lipophilicity. Phenylacetylglycines only showed a small variation in logK(i) values, indicating that insertion of a CH2 group between the r ing and the carbonyl practically abolishes the influence of the ring a nd its substituents. In conclusion, both hydrophobic and electronic pr operties are important determinants of affinity for the PAH transport system. An additional partially negative hydroxyl group in the ring, l ocated preferably at the 3- or 4-position, increases the interaction w ith the transport system.