Transport of anionic drugs across the basolateral membrane of proximal S2 segments of the rabbit kidney. Inverse relationship between the affinity to the p-aminohippurate transport system and the transport rate.

Abstract

The renal p-aminohippurate (PAH) transport system, which resides in the S2 segments of proximal tubules, is a main tubular secretory system for drugs. Previous studies have shown that the hydrophobicity of drugs is positively correlated with their affinity for the basolateral PAH transporter. Affinity was deduced from inhibition of tubular 3H-PAH uptake. However, up to now, no studies are available which tested the relationship between hydrophobicity and transport rate of drugs. Therefore, in the present study, the basolateral transport rates of several drugs (probenecid, CAS 57-66-9, furosemide, CAS 54-31-9, bumetanide, CAS 28395-03-1, mefruside, CAS 7195-27-9) which are substrates of the PAH transporter and which differ markedly regarding their hydrophobic properties (log P values ranging from 1-3) were determined on non-perfused proximal S2 segments microdissected from rabbit kidneys without the use of enzymatic solutions. To measure the transport rate advantage of the finding was taken that the PAH transporter in the basolateral membrane of proximal S2 segments acts as a countertransporter which exchanges PAH with dicarboxylates (glutarate or alpha-keto-glutarate). Hence, the stimulatory effect of a drug on the 14C-glutarate efflux rate of 14C-glutarate preloaded S2 segments is a measure of its translocation across the basolateral cell membrane. The results revealed that with increasing hydrophobicity (mefruside < furosemide < bumetanide < probenecid) the stimulating effect of the drugs on 14C-glutarate efflux decreased indicating that the compounds are more slowly translocated although their potency to inhibit 3H-PAH uptake increased. Thus, an inverse relationship between hydrophobicity and hence affinity of the drugs for the PAH transporter and transport rate could be established.