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{{Short description|Chemical compound}} |
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{{Drugbox |
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{{Infobox drug |
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| verifiedrevid = 459812016 |
| verifiedrevid = 459812016 |
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| IUPAC_name = 4-(dipropylsulfamoyl)benzoic acid |
| IUPAC_name = 4-(dipropylsulfamoyl)benzoic acid |
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| MedlinePlus = a682395 |
| MedlinePlus = a682395 |
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| pregnancy_category = |
| pregnancy_category = |
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| legal_status = |
| legal_status = Rx only |
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| routes_of_administration = |
| routes_of_administration = [[Oral administration|By mouth]] |
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<!--Pharmacokinetic data--> |
<!--Pharmacokinetic data--> |
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| bioavailability = |
| bioavailability = |
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| metabolism = |
| metabolism = |
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| elimination_half-life = 2-6 hours (dose: 0.5-1 g) |
| elimination_half-life = 2-6 hours (dose: 0.5-1 g) |
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| excretion = |
| excretion = kidney (77-88%) |
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<!--Identifiers--> |
<!--Identifiers--> |
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| CAS_number_Ref = {{cascite|correct|??}} |
| CAS_number_Ref = {{cascite|correct|??}} |
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<!--Chemical data--> |
<!--Chemical data--> |
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| C=13 | H=19 | N=1 | O=4 | S=1 |
| C=13 | H=19 | N=1 | O=4 | S=1 |
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| molecular_weight = 285.36 g/mol |
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| smiles = O=S(=O)(N(CCC)CCC)c1ccc(C(=O)O)cc1 |
| smiles = O=S(=O)(N(CCC)CCC)c1ccc(C(=O)O)cc1 |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = DBABZHXKTCFAPX-UHFFFAOYSA-N |
| StdInChIKey = DBABZHXKTCFAPX-UHFFFAOYSA-N |
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}} |
}} |
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'''Probenecid''', also sold under the |
'''Probenecid''', also sold under the brand name '''Probalan''', is a medication that increases [[uric acid]] excretion in the [[urine]]. It is primarily used in treating [[gout]] and [[hyperuricemia]]. |
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Probenecid was developed as an alternative to caronamide<ref name="pmid13171805">{{cite journal | |
Probenecid was developed as an alternative to caronamide<ref name="pmid13171805">{{cite journal | vauthors = Mason RM | title = Studies on the effect of probenecid (benemid) in gout | journal = Annals of the Rheumatic Diseases | volume = 13 | issue = 2 | pages = 120–130 | date = June 1954 | pmid = 13171805 | pmc = 1030399 | doi = 10.1136/ard.13.2.120 }}</ref> to competitively inhibit renal excretion of some drugs, thereby increasing their plasma concentration and prolonging their effects. |
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==Medical uses== |
==Medical uses== |
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Probenecid is primarily used to treat [[gout]] and [[hyperuricemia]]. |
Probenecid is primarily used to treat [[gout]] and [[hyperuricemia]]. |
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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.<ref>{{cite journal| |
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.<ref>{{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 }}</ref> |
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It has also found use as a [[masking agent]],<ref name="pmid17027009">{{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= |
It has also found use as a [[masking agent]],<ref name="pmid17027009">{{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 }}</ref> potentially helping athletes using performance-enhancing substances to avoid detection by drug tests. |
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==Adverse effects== |
==Adverse effects== |
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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]], [[leukemia]] and [[encephalopathy]] are extremely rare.<ref name="pmid25392987">{{cite journal |vauthors=Kydd AS, Seth R, Buchbinder R, Edwards CJ, Bombardier C |title=Uricosuric medications for chronic gout |journal=Cochrane Database |
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.<ref name="pmid25392987">{{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 }}</ref> Theoretically probenecid can increase the risk of uric acid [[kidney stones]]. |
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==Drug interactions== |
==Drug interactions== |
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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.<ref name="pmid7011657">{{cite journal |vauthors=Cunningham RF, Israili ZH, Dayton PG | title = Clinical pharmacokinetics of probenecid | journal = |
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.<ref name="pmid7011657">{{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 }}</ref> |
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==Pharmacology== |
==Pharmacology== |
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===Pharmacodynamics=== |
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⚫ | Probenecid |
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In gout, probenecid competitively inhibits the reabsorption of uric acid through the [[Organic anion-transporting polypeptide|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,<ref>{{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}}</ref> thus reducing blood uric acid levels and reducing its deposition in various tissues. |
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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-transporting polypeptide|organic anion transporter]] (OAT), which reclaims uric acid from the urine and returns it to the plasma.<ref name="pmid2962517">{{cite journal |vauthors=Hsyu PH, Gisclon LG, Hui AC, Giacomini KM |title=Interactions of organic anions with the organic cation transporter in renal BBMV |journal=Am. J. Physiol. |volume=254 |issue=1 Pt 2 |pages=F56–61 |date=January 1988 |pmid=2962517 |doi= 10.1152/ajprenal.1988.254.1.F56}}</ref> 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. |
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⚫ | Probenecid also inhibits [[pannexin|pannexin 1]].<ref name="pmid18596212">{{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 }}</ref> Pannexin 1 is involved in the activation of [[inflammasome]]s and subsequent release of [[interleukin 1 beta|interleukin-1β]] causing inflammation. Inhibition of pannexin 1 thus reduces [[inflammation]], which is the core pathology of gout.<ref name="pmid18596212" /> |
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⚫ | |||
Historically, probenecid has been used to increase the duration of action of drugs such as penicillin and other [[beta-lactam antibiotic]]s. 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.<ref>{{cite book | vauthors = Ho RH | chapter = 4.25 - Uptake Transporters |date= January 2010 | doi = 10.1016/B978-0-08-046884-6.00425-5 | title = Comprehensive Toxicology | edition = Second |pages=519–556 | veditors = McQueen CA, Kim RB |place=Oxford |publisher=Elsevier |language=en |isbn=978-0-08-046884-6 }}</ref> |
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⚫ | |||
⚫ | |||
⚫ | |||
==History== |
==History== |
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During World War II, probenecid was used to extend limited supplies of [[penicillin]] |
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.<ref>{{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 }}</ref> |
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Probenecid was added to the [[International Olympic Committee]]'s list of banned substances in January 1988.<ref>{{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}}</ref> |
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==See also== |
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*[[Probenecid and colchicine]] |
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==References== |
== References == |
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{{Reflist}} |
{{Reflist|30em}} |
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{{Antigout preparations}} |
{{Antigout preparations}} |
Revision as of 19:40, 31 December 2023
Clinical data | |
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Trade names | Probalan |
AHFS/Drugs.com | Monograph |
MedlinePlus | a682395 |
Routes of administration | By mouth |
ATC code | |
Legal status | |
Legal status |
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Pharmacokinetic data | |
Protein binding | 75-95% |
Elimination half-life | 2-6 hours (dose: 0.5-1 g) |
Excretion | kidney (77-88%) |
Identifiers | |
| |
CAS Number | |
PubChem CID | |
IUPHAR/BPS | |
DrugBank | |
ChemSpider | |
UNII | |
KEGG | |
ChEMBL | |
CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.000.313 |
Chemical and physical data | |
Formula | C13H19NO4S |
Molar mass | 285.36 g·mol−1 |
3D model (JSmol) | |
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(verify) |
Probenecid, also sold under the brand name Probalan, is a medication that increases uric acid excretion in the urine. It is primarily used in treating gout and hyperuricemia.
Probenecid was developed as an alternative to caronamide[1] to competitively inhibit renal excretion of some drugs, thereby increasing their plasma concentration and prolonging their effects.
Medical uses
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.[2]
It has also found use as a masking agent,[3] potentially helping athletes using performance-enhancing substances to avoid detection by drug tests.
Adverse 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.[4] Theoretically probenecid can increase the risk of uric acid kidney stones.
Drug 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.[5]
Pharmacology
Pharmacodynamics
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,[6] thus reducing blood uric acid levels and reducing its deposition in various tissues.
Probenecid also inhibits pannexin 1.[7] 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.[7]
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.[8]
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.[9]
Probenecid was added to the International Olympic Committee's list of banned substances in January 1988.[10]
References
- ^ Mason RM (June 1954). "Studies on the effect of probenecid (benemid) in gout". Annals of the Rheumatic Diseases. 13 (2): 120–130. doi:10.1136/ard.13.2.120. PMC 1030399. PMID 13171805.
- ^ Cox VC, Zed PJ (March 2004). "Once-daily cefazolin and probenecid for skin and soft tissue infections". The Annals of Pharmacotherapy. 38 (3): 458–463. doi:10.1345/aph.1d251. PMID 14970368. S2CID 11449580.
- ^ 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". Journal of Chromatography A. 1135 (2): 219–229. doi:10.1016/j.chroma.2006.09.034. hdl:2318/40201. PMID 17027009. S2CID 20282106.
- ^ Kydd AS, Seth R, Buchbinder R, Edwards CJ, Bombardier C (November 2014). "Uricosuric medications for chronic gout". The Cochrane Database of Systematic Reviews (11): CD010457. doi:10.1002/14651858.CD010457.pub2. PMID 25392987.
- ^ Cunningham RF, Israili ZH, Dayton PG (March–April 1981). "Clinical pharmacokinetics of probenecid". Clinical Pharmacokinetics. 6 (2): 135–151. doi:10.2165/00003088-198106020-00004. PMID 7011657. S2CID 24497865.
- ^ "Probenecid". PubChem. U.S. National Library of Medicine. Retrieved 2022-06-12.
- ^ a b Silverman W, Locovei S, Dahl G (September 2008). "Probenecid, a gout remedy, inhibits pannexin 1 channels". American Journal of Physiology. Cell Physiology. 295 (3): C761–C767. doi:10.1152/ajpcell.00227.2008. PMC 2544448. PMID 18596212.
- ^ Ho RH (January 2010). "4.25 - Uptake Transporters". In McQueen CA, Kim RB (eds.). Comprehensive Toxicology (Second ed.). Oxford: Elsevier. pp. 519–556. doi:10.1016/B978-0-08-046884-6.00425-5. ISBN 978-0-08-046884-6.
- ^ Butler D (November 2005). "Wartime tactic doubles power of scarce bird-flu drug". Nature. 438 (7064): 6. Bibcode:2005Natur.438....6B. doi:10.1038/438006a. PMID 16267514.
- ^ Wilson W, Derse E, eds. (2001). Doping in Elite Sport: The Politics of Drugs in the Olympic Movement. Human Kinetics. p. 86. ISBN 0-7360-0329-0.