Пробенецидом химические свойства, назначение, производство
Описание
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.
Химические свойства
White to Off-White Solid
Использование
It is a uricosuric drug, that is, it increases uric acid excretion in the urine. It is primarily used in treating gout and hyperuricemia. Probenecid was developed as an alternative to caronamide to competitively inhibit renal excretion of some drugs, thereby increasing their plasma concentration and prolonging their effects.
Показания
When probenecid (ColBENEMID) is given in sufficient
amounts, it will block the active reabsorption of uric acid
in the proximal tubules following its glomerular filtration,
thereby increasing the amount of urate eliminated.
In contrast, low dosages of probenecid appear to compete
preferentially with plasma uric acid for the proximal
tubule anionic transport system and thereby block
its access to this active secretory system. The uricosuric
action of probenecid, however, is accounted for by the
drug’s ability to inhibit the active reabsorption of filtered
urate.
Определение
ChEBI: A sulfonamide in which the nitrogen of 4-sulfamoylbenzoic acid is substituted with two propyl groups.
Общее описание
Probenecid (Benemid) is the most widely used uricosuricagent in the United States. It is selectively excreted into therenal tubules by OATS. It is extensively metabolized via Ndealkylationor ω-oxidation, followed by phase II conjugationinto the active metabolite, p-sulfamyl hippurate, whichexhibits a high affinity, similar to p-aminohippurate, forbinding to OATS, thereby preventing uric acid reabsorptionfrom the renal proximal tubules.
Реакции воздуха и воды
Insoluble in water.
Профиль реактивности
Probenecid may be light sensitive .
Пожароопасность
Flash point data for Probenecid are not available. Probenecid is probably combustible.
Механизм действия
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.
Фармакокине?тика
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.
Клиническое использование
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.
Побочные эффекты
The major side effect is GI distress (e.g., nausea,
vomiting, and anorexia), but these occur in only 2% of patients at low doses. Other effects include headache,
dizziness, urinary frequency, hypersensitivity reactions, sore gums, and anemia.
Пробенецидом препаратная продукция и сырье
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