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Renal proximal tubules secrete p-aminohippurate (PAH) and other endogenous anionic metabolites into the urine. The extent to which organic anion excretion is regulated is unknown, but recent studies indicate that peritubular serum proteins may have a role. We determined the relative effects of serum proteins and metabolic substrates (citrate, lactate, and alanine) on net PAH secretion in isolated perfused rabbit S2 proximal tubules. Net PAH secretion was calculated from the bath-to-lumen flux of [3H]PAH and the isotope specific activity. We corrected the flux for the important difference in PAH binding between rabbit serum proteins and bovine serum albumin (BSA); rabbit serum proteins (5.7 g/dl) and BSA (6 g/dl) bound 10 microM PAH 21 and 37%, respectively. BSA had no effect, but rabbit serum proteins reversibly inhibited PAH secretion in the presence of metabolic substrates in the bath (40.8%), the perfusate (42.6%), and both media (31.5%). In the absence of metabolic substrates, rabbit serum proteins decreased PAH secretion by only 16.8%. PAH secretion was inhibited by 1 g/dl rabbit serum proteins as effectively as 5.7 g/dl (30.3 and 31.5%, respectively), indicating that PAH transport is very sensitive to inhibition by rabbit serum proteins. In the absence of rabbit serum proteins, metabolic substrates in the bath had no effect on PAH secretion. We conclude that rabbit serum proteins inhibit basolateral membrane transport of PAH in proximal tubules. Inhibition by serum proteins is enhanced by bath or lumen citrate, alanine, and lactate, suggesting that peritubular plasma proteins and tubule cell metabolism may interact to modulate proximal tubule organic anion secretion and urinary excretion.