General Description
Odorless white or almost white crystalline powder. Slightly bitter taste; pleasant aftertaste.
Reactivity Profile
PROBENECID(57-66-9) may be light sensitive .
Air & Water Reactions
Insoluble in water.
Fire Hazard
Flash point data for this chemical are not available. PROBENECID is probably combustible.
Description
Probenecid is insoluble in water and acidic solutions but is soluble in alkaline solutions buffered to pH 7.4.
Probenecid initially was synthesized as a result of studies in the 1940s on sulfonamides that indicated the
sulfonamides decreased the renal clearance of penicillin, extending the half-life of penicillin as supplies diminished.
Probenecid thus was initially used—and is still indicated—for that purpose. Probenecid promotes the excretion of
uric acid by inhibiting the urate anion exchange transporter (URAT 1), decreasing the reabsorption of uric acid in the
proximal tubules. The overall effect is to decrease plasma uric acid concentrations, thereby decreasing the rate and
extent of urate crystal deposition in joints and synovial fluids. Within the series of N-dialkylsulfamyl benzoates from
which probenecid is derived, renal clearance of these compounds is decreased as the length of the N-alkyl
substituents is increased. Uricosuric activity increases with increasing size of the alkyl group in the series methyl,
ethyl, and propyl.
Definition
ChEBI: A sulfonamide in which the nitrogen of 4-sulfamoylbenzoic acid is substituted with two propyl groups.
Brand name
Benemid (Merck); Probalan (Lannett).
Mechanism of action
Probenecid is rapidly absorbed after oral administration,
with peak plasma levels usually reached in 2 to 4
hours. Its half-life is somewhat variable (6–12 hours) because
of both its extensive plasma protein binding and
its active proximal tubular secretion. Since tubular backdiffusion
is decreased at alkaline urinary pH ranges,
probenecid excretion increases with increasing urinary
pH. Probenecid is rapidly metabolized, with less than
5% of an administered dose being eliminated in 24
hours.The major metabolite is an acyl monoglucuronide.
Pharmacokinetics
Probenecid is essentially completely absorbed from the GI tract on oral administration, with peak plasma levels
observed within 2 to 4 hours. Like most acidic compounds, probenecid (pKa = 3.4) is extensively plasma protein
bound (93–99%). The primary route of elimination of probenecid and its metabolites is the urine. It is extensively
metabolized in humans, with only 5 to 10% being excreted as unchanged drug. The major metabolites detected result
from glucuronide conjugation of the carboxylic acid, ω-oxidation of the n-propyl side chain and subsequent oxidation
of the resulting alcohol to the carboxylic acid derivative, ω1-oxidation of the n-propyl group, and N-dealkylation.
Clinical Use
Probenecid is an effective and relatively safe agent
for controlling hyperuricemia and preventing tophi
deposition in tissues. Chronic administration will decrease
the incidence of acute gouty attacks as well as diminish
the complications usually associated with hyperuricemia,
such as renal damage and tophi deposition.
Probenecid is still used by some physicians to maintain
high blood levels of penicillin, cephalosporin, acyclovir,
and cyclosporine. It is not useful in treating acute attacks
of gouty arthritis. If the total amount of uric acid
excreted is greater than 800 mg/day, the urine should be
alkalinized to prevent kidney stone formation and promote
uric acid.
Veterinary Drugs and Treatments
Although there has been very limited clinical use or research on
probenecid in veterinary medicine, it can be useful in treating gout
(hyperuricemia), particularly in reptiles.
Probenecid’s effect in inhibiting renal tubular secretion of certain
beta-lactam antibiotics and other weak organic acids is of interest
for increasing serum concentrations, or reducing doses and dosing
frequency of these drugs. This may allow greater efficacy (but also
toxic effects) and reduce the cost or dosing frequency of expensive
human drugs. Probenecid has a significantly long elimination halflife
in dogs (about 18 hours), which may make it particularly useful
in this species; however, at present there is little research supporting
this use of probenecid in veterinary patients.
