probenecid

Probenecid is primarily used to treat gout and hyperuricemia.

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.{{cite journal | vauthors = Cox VC, Zed PJ | title = Once-daily cefazolin and probenecid for skin and soft tissue infections | journal = The Annals of Pharmacotherapy | volume = 38 | issue = 3 | pages = 458–463 | date = March 2004 | pmid = 14970368 | doi = 10.1345/aph.1d251 | s2cid = 11449580 }}

It has also found use as a masking agent,{{cite journal | vauthors = Morra V, Davit P, Capra P, Vincenti M, Di Stilo A, Botrè F | title = 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 | journal = Journal of Chromatography A | volume = 1135 | issue = 2 | pages = 219–229 | date = December 2006 | pmid = 17027009 | doi = 10.1016/j.chroma.2006.09.034 | hdl-access = free | s2cid = 20282106 | hdl = 2318/40201 }} potentially helping athletes using performance-enhancing substances to avoid detection by drug tests.

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.{{cite journal | vauthors = Kydd AS, Seth R, Buchbinder R, Edwards CJ, Bombardier C | title = Uricosuric medications for chronic gout | journal = The Cochrane Database of Systematic Reviews | issue = 11 | pages = CD010457 | date = November 2014 | pmid = 25392987 | doi = 10.1002/14651858.CD010457.pub2 | doi-access = free | pmc = 11262558 }} Theoretically probenecid can increase the risk of uric acid kidney stones.

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.{{cite journal | vauthors = Cunningham RF, Israili ZH, Dayton PG | title = Clinical pharmacokinetics of probenecid | journal = Clinical Pharmacokinetics | volume = 6 | issue = 2 | pages = 135–151 | date = March–April 1981 | pmid = 7011657 | doi = 10.2165/00003088-198106020-00004 | s2cid = 24497865 }}

In gout, probenecid competitively inhibits the reabsorption of uric acid through the organic anion transporter (OAT) at the proximal tubules. This leads to preferential reabsorption of probenecid back into plasma and excretion of uric acid in urine,{{Cite web | work = PubChem |title=Probenecid |url=https://pubchem.ncbi.nlm.nih.gov/compound/4911 |access-date=2022-06-12 | publisher = U.S. National Library of Medicine |language=en}} thus reducing blood uric acid levels and reducing its deposition in various tissues.

Probenecid also inhibits pannexin 1.{{cite journal | vauthors = Silverman W, Locovei S, Dahl G | title = Probenecid, a gout remedy, inhibits pannexin 1 channels | journal = American Journal of Physiology. Cell Physiology | volume = 295 | issue = 3 | pages = C761–C767 | date = September 2008 | pmid = 18596212 | pmc = 2544448 | doi = 10.1152/ajpcell.00227.2008 }} Pannexin 1 is involved in the activation of inflammasomes and subsequent release of interleukin-1β causing inflammation. Inhibition of pannexin 1 thus reduces inflammation, which is the core pathology of gout.

In the kidneys, probenecid is filtered at the glomerulus, secreted in the proximal tubule and reabsorbed in the distal tubule. Probenicid lowers the concentration of certain drugs in urine drug screens by reducing renal excretion of these drugs.

Historically, probenecid has been used to increase the duration of action of drugs such as penicillin and other beta-lactam antibiotics. Penicillins are excreted in the urine at proximal and distal convoluted tubules through the same organic anion transporter (OAT) as seen in gout. Probenecid competes with penicillin for excretion at the OAT, which in turn increases the plasma concentration of penicillin.{{cite book |title=Comprehensive Toxicology |vauthors=Ho RH |date=January 2010 |publisher=Elsevier |isbn=978-0-08-046884-6 |veditors=McQueen CA, Kim RB |edition=Second |place=Oxford |pages=519–556 |language=en |chapter=4.25 - Uptake Transporters |doi=10.1016/B978-0-08-046884-6.00425-5}}

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.{{cite journal | vauthors = Butler D | title = Wartime tactic doubles power of scarce bird-flu drug | journal = Nature | volume = 438 | issue = 7064 | pages = 6 | date = November 2005 | pmid = 16267514 | doi = 10.1038/438006a | doi-access = free | bibcode = 2005Natur.438....6B }}

Probenecid was added to the International Olympic Committee's list of banned substances in January 1988, due to its use as a masking agent.{{cite book|title=Doping in Elite Sport: The Politics of Drugs in the Olympic Movement|url=https://books.google.com/books?id=wi2d4YyLh3wC&pg=PA86| veditors = Wilson W, Derse E |page=86|year=2001|publisher=Human Kinetics|isbn=0-7360-0329-0}}

{{Reflist|30em}}

{{Antigout preparations}}

Category:Antigout agents

Category:World Anti-Doping Agency prohibited substances

Category:Benzoic acids