The binding of uric acid to
plasma proteins is relatively small and probably does not have great
physiological significance. However, even this limited binding may be affected
by administration of drugs, such as salicylates, phenylbutazone, probenecid,
and sulfinpyrazone. These drugs probably affect urate protein binding only
sec-ondarily; that is, their principal action is to interfere with renal
transport of uric acid, which in turn leads to alterations in plasma urate
The renal mechanisms involved
in the handling of uric acid are complex and involve filtration, reabsorp-tion,
secretion, and possibly postsecretory reabsorption. The proximal tubule is the
principal site of both carrier-mediated reabsorption and secretion of urate.
Urate is believed to be transported from the ultrafiltrate to the intracellular
space by an anion (hydroxyl, bicarbonate, chloride, or lactate) exchange
mechanism in the luminal membrane. This active transport system
can be inhib-ited by drugs, such as probenecid, sulfinpyrazone, and salicylate.
The urate accumulated in the cell moves pas-sively across the basolateral
membrane and into the peritubular fluid down its electrochemical gradient.
Conversely, active tubular secretion of urate occurs as a consequence of
carrier-mediated transport across the basolateral
membrane of the proximal tubule. The urate accumulated in the cell moves passively across the lu-minal
membrane into the ultrafiltrate along its concen-tration gradient. The
carrier-mediated secretion of urate can be inhibited by a variety of organic
anions, includ-ing the thiazide and loop diuretics.
The intracellular concentration
of urate in the proxi-mal tubule will ultimately be determined by the balance
of influx and efflux. When the transport of urate from the peritubular fluid is high, there is a net elimination of urate
across the luminal membrane. In contrast, when the transport of urate from luminal fluid is high, there is a net
reabsorption across the basolateral membrane.
Urate excretion is subject to
modification by a vari-ety of organic anions, including uricosuric agents, phenylbutazone,
diuretics, radiographic contrast agents, and certain anticancer compounds. A
further complicat-ing feature is that drug effects may be biphasic; that is,
small amounts may depress urate excretion, while larger doses have uricosuric