Probenecid

Pharmaceuticals

Pharmaceuticals -> Listed in ZINC15

2.3

3.21

CRYSTALS FROM DIL ALCOHOL

WHITE OR NEARLY WHITE, FINE, CRYSTALLINE POWDER

less than 1 mg/mL at 68 °F (NTP, 1992)

FREELY SOL IN WATER /SODIUM SALT/

SOL IN DIL ALKALI, ALCOHOL, CHLOROFORM & ACETONE; PRACTICALLY INSOL IN WATER & DIL ACIDS

4.25e-01 g/L

>42.8 [ug/mL] (The mean of the results at pH 7.4)

Breast Feeding; Lactation; Antigout Agents; Gout Suppressants; Sulfonamides; Uricosuric Agents

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

381 to 385 °F (NTP, 1992)

194-196 °C

195 °C

Probenecid appears as odorless white or almost white crystalline powder. Slightly bitter taste; pleasant aftertaste. (NTP, 1992)

Solid

Probenecid tablets should be stored in well closed containers at a temperature less than 40 °C, preferably between 15-30 °C. Commercially available preparations containing probenecid and colchicine should be protected from light. Following the date of manufacture, commercially available probenecid tablets have an expiration date of 3-5 yr depending on the packaging.

Warning

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

P264, P270, P301+P317, P330, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 81 reports by companies from 5 notifications to the ECHA C&L Inventory.

SYMPTOMS: Symptoms of exposure to this chemical include nausea, vomiting, headache, sore gums, flushing, dizziness, urinary frequency and anemia. On rare occasions an anaphylactic reaction or a hypersensitivity reaction with fever, dermatitis and pruritis has occurred, and there have been reports of hepatic necrosis, the nephrotic syndrome and aplastic anemia. Exposure may precipitate an acute attack of gout, and renal colic or renal calculi with or without hematuria may occur. It may also cause gastrointestinal upset. Other symptoms include urticaria, nephrosis, coma and status epilepticus. In massive overdosage, stimulation of the central nervous system with convulsions and death from respiratory failure may occur. Exposure may also cause increased plasma concentrations of methotrexate, costovertebral pain, precipitation of acute gouty arthritis, anorexia, leukopenia, alopecia and hemolytic anemia (which could be related to genetic deficiency of glucose-6-phosphate dehydrogenase in red blood cells). It may also cause skin rashes. It may occasionally cause drug fever. Jaundice, asthma and eosinophilia have preceded a massive hepatic necrosis.

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl probenecid, approved on the basis of safety and effectiveness by FDA under sections 505 and 507 of the Federal Food, Drug, and Cosmetic Act.

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

SMALL SPILLS AND LEAKAGE: If a spill of this chemical occurs, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with acetone and transfer the dampened material to a suitable container. Use absorbent paper dampened with acetone to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with acetone followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

PROBENECID INHIBITS RENAL TRANSPORT OF ... PANTOTHENIC ACID, IODOMETHAMATE & RELATED IODINATED ORG ACIDS, AMINOHIPPURIC ACID, 17-KETOSTEROIDS PHENOLSULFONPHTHALEIN & SULFOBROMOPHTHALEIN. DOSAGE OF THESE AGENTS ... SHOULD BE MODIFIED WHEN THEY ARE ADMIN WITH PROBENECID. ... /IT ALSO/ INCR RENAL EXCRETION OF OXIPURINOL ... .

CONCURRENT ADMIN OF CEPHALEXIN & PROBENECID RESULTS IN HIGHER & PROLONGED SERUM ANTIBIOTIC LEVELS. ... CONCURRENT THERAPY DOES NOT APPEAR TO HAVE ANY CLINICAL ADVANTAGE OVER INCR IN ANTIBIOTIC DOSE.

/IN ADDN TO CEPHALEXIN/ OTHER CEPHALOSPORIN ANALOGS WHOSE SERUM LEVELS ARE ENHANCED BY PROBENECID ARE CEFAZOLIN, CEPHACETRILE, CEPHALOGLYCIN, CEPHALORIDINE, CEPHALOTHIN & CEPHRADINE.

CONCURRENT ADMIN OF PROBENECID, PARTICULARLY IN HIGH DOSES, DECR RENAL CLEARANCE OF NITROFURANTOIN & INCR SERUM LEVEL. ... INTERACTION MAY LEAD TO NITROFURANTOIN-INDUCED TOXICITY (EG, POLYNEUROPATHIES) OR DECR NITROFURANTOIN EFFICACY AS URINARY TRACT ANTI-INFECTIVE AGENT.

For more Interactions (Complete) data for PROBENECID (55 total), please visit the HSDB record page.

There are no reports on the frequency of liver test abnormalities during probenecid therapy, but they are probably rare as the drug is largely secreted unchanged in the urine. A single case report of a severe hypersensitivity reaction from probenecid and rechallenge with a rapid and severe recurrence of jaundice was reported over 50 years ago. As is typical for hypersensitivity reactions, the onset was within days of starting probenecid and was accompanied by fever and rash.

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical. [http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=57-66-9]

HUGE OVERDOSAGE OF PROBENECID RESULTS IN STIMULATION OF CNS, CONVULSIONS, & DEATH FROM RESP FAILURE.

... /OCCASIONALLY/ PATIENTS MAY EXPERIENCE ANOREXIA, NAUSEA, VOMITING, URINARY FREQUENCY, HYPERSENSITIVITY REACTIONS, SORE GUMS, FLUSHING, DIZZINESS & ANEMIA. NEPHROTIC SYNDROME, HEPATIC NECROSIS & APLASTIC ANEMIA OCCUR RARELY.

The most frequent adverse effects include headache, anorexia, nausea, and vomiting. Other reported adverse effects include dizziness, flushing, sore gums, alopecia, urinary frequency, leukopenia, and anemia. Nephrotic syndrome, hepatic necrosis, and aplastic anemia occur rarely. Mild to moderately severe hemolytic anemia, which in some patients could be related to genetic deficiency of glucose-6-phosphate dehydrogenase, has also been reported.

Hypersensitivity reactions which may be characterized by dermatitis, pruritus, fever, sweating, hypotension, and anaphylactic reaction occur rarely. Most cases of severe allergic reactions and anaphylaxis have been reported to occur within several hours after administration in patients who had previously received the drug. If a hypersensitivity reaction occurs in patients receiving probenecid, the drug should be discontinued. If rash occurs during administration of penicillin with probenecid and the causative agent cannot be determined, discontinuance of both drugs may be necessary.

For more Human Toxicity Excerpts (Complete) data for PROBENECID (7 total), please visit the HSDB record page.

Probenecid

TR-395: Toxicology and Carcinogenesis Studies of Probenecid (CASRN 57-66-9) in F344/N Rats and B6C3F1 Mice (Gavage Studies) (1991 )

11/20/90

No Evidence

No Evidence

No Evidence

Drug Induced Liver Injury Rank (DILIrank 2.0)

Probenecid

Ambiguous-DILI-concern

6

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

... /STUDIES HAVE SHOWN THAT PROBENECID BLOCKS/ THE TRANSPORT SYSTEM FOR ELIMINATION OF 5-HYDROXYINDOLEACETIC ACID (5HIAA) FROM BRAIN IN RATS.

Probenecid was tested for mutagenicity in the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program. Probenecid was tested at doses of 0.033, 0.10, 0.33, 1.0, and 3.3 mg/plate in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat or hamster liver S-9. Probenecid was negative in these tests and the highest ineffective dose tested in any Salmonella typhimurium strain mg/plate.

... Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenic activity of probenecid for male or female F344/N rats receiving 100 or 400 mg/kg in corn oil. There was no evidence of carcinogenic activity of probenecid for male B6C3F1 mice given 100 or 400 mg/kg probenecid in corn oil. There was some evidence of carcinogenic activity of probenecid for female B6C3F1 mice based on an increased incidence of hepatocellular adenomas.

... Toxicology and carcinogenicity studies were conducted by administering probenecid (>99% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex ... 5 days/wk ... for ... 2 yr. ... Doses of 0, 100, and 400 mg/kg were used for the 2 yr studies in rats and mice. These doses were administered once daily, 5 days/wk for up to 103 wk to groups of 50 males or 50 females of each species. Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenic activity of probenecid for male or female F344/N rats receiving 100 or 400 mg/kg in corn oil. There was no evidence of carcinogenic activity of probenecid for male B6C3F1 mice given 100 or 400 mg/kg probenecid in corn oil. There was some evidence of carcinogenic activity of probenecid for female B6C3F1 mice based on an increased incidence of hepatocellular adenomas.

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl probenecid, approved on the basis of safety and effectiveness by FDA under sections 505 and 507 of the Federal Food, Drug, and Cosmetic Act.

M - Musculo-skeletal system

QM - Musculo-skeletal system

Probenecid is a uricosuric and renal tubular blocking agent and is used in combination with colchicine to treat chronic gouty arthritis when complicated by frequent, recurrent acute attacks of gout. It inhibits the reabsorption of urate at the proximal convoluted tubule, thus increasing the urinary excretion of uric acid and decreasing serum urate levels. Effective uricosuria reduces the miscible urate pool, retards urate deposition, and promotes resorption of urate deposits. At the proximal and distal tubles, probenecid competitively inhibits the secretion of many weak organic acids including penicillins, most cephalosporins, and some other β-lactam antibiotics. This results in an increase in the plasma concentrations of acidic drugs eliminated principally by renal secretion, but only a slight increase if the drug is eliminated mainly by filtration. Thus, the drug can be used for therapeutic advantages to increase concentrations of certain β-lactam antibiotics in the treatment of gonorrhea, neurosyphilis, or pelvic inflammatory disease (PID).

Probenecid inhibits the tubular reabsorption of urate, thus increasing the urinary excretion of uric acid and decreasing serum urate levels. Probenecid may also reduce plasma binding of urate and inhibit renal secretion of uric acid at subtherapeutic concentrations. The mechanism by which probenecid inhibits renal tubular transport is not known, but the drug may inhibit transport enzymes that require a source of high energy phosphate bonds and/or nonspecifically interfere with substrate access to protein receptor sites on the kidney tubules.

IN HIGHER DOSES THAN ARE REQUIRED FOR URICOSURIC EFFECT, PROBENECID ALSO INHIBITS TRANSPORT OF ORG ACIDS AT OTHER SITES, IE, TRANSPORT SYSTEM THAT REMOVES ORG ACIDS FROM CEREBROSPINAL FLUID.

IT INHIBITS TUBULAR REABSORPTION OF URATE, THUS INCR URINARY EXCRETION OF URIC ACID & DECR SERUM URIC ACID LEVELS.

Probenecid is a renal tubular blocking agent. The drug competitively inhibits active reabsorption of uric acid at the proximal convoluted tubule, thus promoting urinary excretion of uric acid and reducing serum urate concentrations. Probenecid may reduce plasma protein binding of urate and, in subtherapeutic doses, may inhibit renal secretion of uric acid. In healthy individuals, probenecid has no effect on the glomerular filtration rate or on the tubular reabsorption of normal urinary constituents such as glucose, arginine, urea, sodium, potassium, chloride, or phosphate.

At the proximal and distal tubules, probenecid competitively inhibits the secretion of many weak organic acids including penicillins, most cephalosporins, and some other beta-lactam antibiotics. In general, the net effect of probenecid on the plasma concentration of weak acids depends on the ratio of the amount of organic acid secreted by the kidneys to that amount filtered at the glomeruli. Thus, probenecid substantially increases plasma concentrations of acidic drugs eliminated principally by renal secretion, but increases plasma concentrations only slightly if the drug is eliminated mainly by filtration. Plasma concentrations of penicillins are often more than doubled by probenecid; the concentration of penicillin in the CSF is also increased. Probenecid also substantially increases plasma concentrations of most cephalosporins and some other beta-lactam antibiotics. In addition, half-lives of the penicillins and cephalosporins are prolonged and their volumes of distribution may be reduced by probenecid. ... The cellular mechanism(s) responsible for the inhibition of renal tubular transport by probenecid is not known. The drug may inhibit transport enzymes that require a source of high energy phosphate bonds and/or nonspecifically interfere with substrate access to protein receptor sites on the kidney tubules.

CSF concentrations of 5-hydroxyindoleacetic acid, homovanillic acid, cyclic adenosine monophosphate, and 4-hydroxy-3-methoxyphenylglycol are elevated following administration of probenecid. It has been proposed that probenecid blocks the active transport of these organic acids from the CSF into blood. Probenecid-induced elevations of homovanillic acid (a dopamine metabolite) in the CSF of patients with parkinsonian syndrome and of 5-hydroxyindoleacetic acid(a metabolite of serotonin) in the CSF of mentally depressed patients are substantially lower than those in healthy patients.

6-12 hours

THE HALF-LIFE OF /PROBENECID/ IN PLASMA IS DOSE DEPENDENT AND VARIES FROM LESS THAN 5 HR TO MORE THAN 8 HR ... .

Following oral administration of 2 g of probenecid, plasma half-life of the drug ranges from 4-17 hr; the half-life decreases as the dose decreases from 2 g to 500 mg.

YIELDS P-DIPROPYLSULFAMOYLBENZOYL-BETA-D-GLUCURONIC ACID; P-(2-HYDROXYPROPYL N-PROPYLSULFAMOYL) BENZOIC ACID; P-(3-HYDROXYPROPYL N-PROPYLSULFAMOYL) BENZOIC ACID; & P-PROPYLSULFAMOYLBENZOIC ACID IN MAN. /FROM TABLE/

STRUCTURES OF ALL OF METAB OF PROBENECID IN RAT BILE & HUMAN URINE HAVE BEEN ELUCIDATED. PROPIONIC ACID HAS NOW BEEN IDENTIFIED AS ANOTHER PROBENECID METAB. MAJOR METABOLIC PATHWAYS INVOLVE SIDE-CHAIN OXIDATION & GLUCURONIDE CONJUGATION ... .

... BETA-GLUCURONIDES OF 2- & 3-HYDROXYLATED METAB & ACYL GLUCURONIDE OF PROBENECID PER SE HAVE NOW BEEN IDENTIFIED. ... THERE IS CONSIDERABLE SPECIES DIFFERENCE IN METABOLISM. IN RATS & MONKEYS OXIDATION IS FAVORED. ... IN DOGS CONJUGATION ... /IS/ MAJOR PATHWAY, WHEREAS IN MAN, OXIDATIVE ... PATHWAY ... IS AS IMPORTANT AS GLUCURONIDATION.

CHRONIC ADMIN OF DRUGS NOT ONLY STIMULATES METAB OF OTHER CMPD, BUT IN SOME INSTANCES PHARMACOLOGICAL OR TOXIC EFFECT OF A DRUG WHEN GIVEN CHRONICALLY, DIMINISHES, BECAUSE IT STIMULATES ITS OWN METABOLISM EXAMPLE OF DRUG THAT EXERT THIS EFFECT IN DOGS ... /IS/ ... PROBENECID ... .

For more Metabolism/Metabolites (Complete) data for PROBENECID (6 total), please visit the HSDB record page.

Agents that aid or increase the action of the principle drug (DRUG SYNERGISM) or that affect the absorption, mechanism of action, metabolism, or excretion of the primary drug (PHARMACOKINETICS) in such a way as to enhance its effects.

Gout suppressants that act directly on the renal tubule to increase the excretion of uric acid, thus reducing its concentrations in plasma.

Excreted principally in the urine as monoacyl glucuronide and unchanged drug. Alkalinization of urine increases renal probenecid excretion.

PROBENECID IS COMPLETELY ABSORBED AFTER ORAL ADMIN. PEAK PLASMA CONCN ARE REACHED IN 2-4 HR. THE HALF-LIFE OF THE DRUG IN PLASMA IS DOSE DEPENDENT AND VARIES FROM LESS THAN 5 HR TO MORE THAN 8 HR.

BETWEEN 85 & 95% OF DRUG IS BOUND TO PLASMA ALBUMIN, LARGELY TO ALBUMIN. SMALL UNBOUND PORTION GAINS ACCESS TO GLOMERULAR FILTRATE; A MUCH LARGER PORTION IS ACTIVELY SECRETED BY PROXIMAL TUBULE.

IN SPITE OF ITS LOW PKA (3.4), HIGH LIPID SOLUBILITY OF UNDISSOCIATED FORM RESULTS IN VIRTUALLY COMPLETE ABSORPTION BY BACK DIFFUSION UNLESS URINE IS MARKEDLY ALKALINE. SMALL AMOUNT OF PROBENECID GLUCURONIDE APPEARS IN URINE.

... /ORG ACID CMPD SUCH AS PROBENECID /ARE/ NOT TAKEN UP SO AVIDLY BY /PARENCHYMATOUS OR RETICULO-ENDOTHELIAL TISSUES/ & EXHIBIT HIGHER PLASMA CONCN ... .

For more Absorption, Distribution and Excretion (Complete) data for PROBENECID (8 total), please visit the HSDB record page.

MEDICATION

Use (kg; approx.) in Germany (2009): >250

(1976) 6.15X10+6 GRAMS (PRINCPL CUSTMS DISTS)

(1978) 9.09X10+6 GRAMS (PRINCPL CUSTMS DISTS)

(1976) PROBABLY GREATER THAN 9.08X10+5 GRAMS

(1978) PROBABLY GREATER THAN 9.08X10+5 GRAMS

REACTION OF TOLUENE WITH CHLOROSULFONIC ACID FOLLOWED BY HYDROLYSIS AND OXIDATION YIELDS P-CARBOXYBENZENESULFONICACID, THEN TREATMENT OF THIS ACID WITH CHLOROSULFONIC ACID AND CONDENSATION WITH DI-N-PROPYLAMINE

PREPARATION FROM P-CARBOXYBENZENESULFONYL CHLORIDE & DIPROPYLAMINE.

PROBENECID (BENEMID, PROBALAN) IS MARKETED AS ORAL TABLETS (500 MG).

Oral Tablets, 500 mg, Benemid (scored), MSD; Probalan, Lannett; Tablets, film coated 500 mg.

Oral For suspension, Ampicillin (trihydrate) 3.5 g (of ampicillin) with Probenecid 1 g, Amplicillin and Probenecid Oral Suspension, Biocraft; Polycillin-BRB, Bristol-Myers; Probampacin, Goldline. /Ampicillin (Trihydrate) and Probenecid/

Oral Tablets 500 mg Probenecid and Colchincine 0.5 mg, ColBENEMID (scored), MSD; Col-Probenecid, Danbury, Goldline, United Research; Proben-C Rugby. /Probencid and Colchicine/

Tablets, 500 mg