Probenecid

Probenecid
Names
Trade namesProbalan
IUPAC name
  • 4-(dipropylsulfamoyl)benzoic acid
Clinical data
Main usesGout[1]
Side effectsHeadache, vomiting, nausea[1]
Routes of
use		By mouth
External links
AHFS/Drugs.comMonograph
US NLMProbenecid
MedlinePlusa682395
Legal
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetics
Protein binding75-95%
Elimination half-life2-6 hours (dose: 0.5-1 g)
Excretionkidney (77-88%)
Chemical and physical data
FormulaC13H19NO4S
Molar mass285.36 g·mol−1
3D model (JSmol)
SMILES
  • O=S(=O)(N(CCC)CCC)c1ccc(C(=O)O)cc1
InChI
  • InChI=1S/C13H19NO4S/c1-3-9-14(10-4-2)19(17,18)12-7-5-11(6-8-12)13(15)16/h5-8H,3-4,9-10H2,1-2H3,(H,15,16) checkY
  • Key:DBABZHXKTCFAPX-UHFFFAOYSA-N checkY

Probenecid, also sold under the brand name Probalan, is a medication primarily used to treat hyperuricemia including in gout.[1] It is also used to decrease the clearance of β-lactam antibiotics and cidofovir.[1] It is taken by mouth.[1]

Common side effects include headache, vomiting, and nausea.[1] Other side effects may include allergic reactions, kidney stones, and a worsened gout attack if started during the attack.[1] Use in pregnancy appears to be safe, though such use has not been well studied.[2] It works by blocking the ability of the kidney to reabsorb urate.[1]

Probenecid was initially developed during World War II to extend penicillin supplies.[3] It was approved for medical use in the United States in 1951 and is available as a generic medication.[1] In the United States 100 tablets of 500 mg costs about 78 USD as of 2021.[4]

Medical uses

Probenecid is primarily used to treat gout and hyperuricemia. It should only be started two to three weeks after a current gout flair has ended.[1]

Probenecid is sometimes used to increase the concentration of some antibiotics and to protect the kidneys when given with cidofovir. Specifically, a small amount of evidence supports the use of intravenous cefazolin once rather than three times a day when it is combined with probenecid.[5]

It has also found use as a masking agent,[6] potentially allowing athletes using performance-enhancing substances to avoid detection by drug tests.

Dosage

In gout it is often used at a dose of 250 mg twice a day for the first week followed by 500 mg twice per day.[1] It is generally started two to three weeks after the last gout attack.[1]

Side effects

Mild symptoms such as nausea, loss of appetite, dizziness, vomiting, headache, sore gums, or frequent urination are common with this medication. Life-threatening side effects such as thrombocytopenia, hemolytic anemia, leukemia and encephalopathy are extremely rare.[7] Theoretically probenecid can increase the risk of uric acid kidney stones.

Interactions

Some of the important clinical interactions of probenecid include those with captopril, indomethacin, ketoprofen, ketorolac, naproxen, cephalosporins, quinolones, penicillins, methotrexate, zidovudine, ganciclovir, lorazepam, and acyclovir. In all these interactions, the excretion of these drugs is reduced due to probenecid, which in turn can lead to increased concentrations of these.[8]

Pharmacology

Probenecid probably has several pharmacological targets, including blocking pannexins.[9] Probenecid is also useful in the treatment of gout where the mechanism of action is believed to be focused on the kidney. Probenecid interferes with the kidneys' organic anion transporter (OAT), which reclaims uric acid from the urine and returns it to the plasma.[10] If probenecid (an organic acid) is present, the OAT binds preferentially to it (instead of to uric acid), preventing reabsorption of the uric acid. Hence, the urine retains more uric acid, lowering uric acid concentration in the plasma. This is a good example of a medical usage for competition between substrates transported across cell membranes. This same effect, however, alters excretion of acidic drugs by the kidney, leading to the many drug interactions noted above.

Pharmacokinetics

In the kidneys, probenecid is filtered at the glomerulus, secreted in the proximal tubule and reabsorbed in the distal tubule.

History

During World War II, probenecid was used to extend limited supplies of penicillin; this use exploited probenecid's interference with drug elimination (via urinary excretion) in the kidneys and allowed lower doses of penicillin to be used.[3]

Probenecid was developed as an alternative to caronamide[11] to competitively inhibit kidney excretion of some drugs, thereby increasing their plasma concentration and prolonging their effects.

Probenecid was added to the International Olympic Committee's list of banned substances in January 1988.[12]

In 2021, a study reported that the drug had broad antiviral properties.[13]

See also

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 "Probenecid Monograph for Professionals". Drugs.com. Archived from the original on 21 January 2021. Retrieved 29 October 2021.
  2. ↑ "Probenecid (Benemid) Use During Pregnancy". Drugs.com. Archived from the original on 29 November 2020. Retrieved 29 October 2021.
  3. 1 2 Butler D (2005). "Wartime tactic doubles power of scarce bird-flu drug". Nature. 438 (7064): 6. doi:10.1038/438006a. PMID 16267514.
  4. ↑ "Probenecid Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 28 January 2021. Retrieved 29 October 2021.
  5. ↑ Cox, VC; Zed, PJ (March 2004). "Once-daily cefazolin and probenecid for skin and soft tissue infections". The Annals of Pharmacotherapy. 38 (3): 458–63. doi:10.1345/aph.1d251. PMID 14970368. S2CID 11449580.
  6. ↑ Morra V, Davit P, Capra P, Vincenti M, Di Stilo A, Botrè F (December 2006). "Fast gas chromatographic/mass spectrometric determination of diuretics and masking agents in human urine: Development and validation of a productive screening protocol for antidoping analysis". J Chromatogr A. 1135 (2): 219–29. doi:10.1016/j.chroma.2006.09.034. PMID 17027009.
  7. ↑ Kydd AS, Seth R, Buchbinder R, Edwards CJ, Bombardier C (November 14, 2014). "Uricosuric medications for chronic gout". Cochrane Database Syst Rev (11): CD010457. doi:10.1002/14651858.CD010457.pub2. PMID 25392987.
  8. ↑ Cunningham RF, Israili ZH, Dayton PG (March–April 1981). "Clinical pharmacokinetics of probenecid". Clin Pharmacokinet. 6 (2): 135–51. doi:10.2165/00003088-198106020-00004. PMID 7011657. S2CID 24497865.
  9. ↑ Silverman W, Locovei S, Dahl G (September 2008). "Probenecid, a gout remedy, inhibits pannexin 1 channels". Am. J. Physiol., Cell Physiol. 295 (3): C761–7. doi:10.1152/ajpcell.00227.2008. PMC 2544448. PMID 18596212.
  10. ↑ Hsyu PH, Gisclon LG, Hui AC, Giacomini KM (January 1988). "Interactions of organic anions with the organic cation transporter in renal BBMV". Am. J. Physiol. 254 (1 Pt 2): F56–61. doi:10.1152/ajprenal.1988.254.1.F56. PMID 2962517.
  11. ↑ MASON RM (June 1954). "Studies on the Effect of Probenecid ('Benemid') in Gout". Ann. Rheum. Dis. 13 (2): 120–30. doi:10.1136/ard.13.2.120. PMC 1030399. PMID 13171805.
  12. ↑ Wilson, Wayne; Derse, Edward, eds. (2001). Doping in Elite Sport: The Politics of Drugs in the Olympic Movement. Human Kinetics. p. 86. ISBN 0-7360-0329-0. Archived from the original on 2021-10-21. Retrieved 2021-09-20.
  13. ↑ Murray, Jackelyn; Hogan, Robert J.; Martin, David E.; Blahunka, Kathy; Sancilio, Fred D.; Balyan, Rajiv; Lovern, Mark; Still, Richard; Tripp, Ralph A. (2021-09-10). "Probenecid inhibits SARS-CoV-2 replication in vivo and in vitro". Scientific Reports. 11 (1): 18085. doi:10.1038/s41598-021-97658-w. ISSN 2045-2322. PMC 8433326. Archived from the original on 2021-09-20. Retrieved 2021-09-20.
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