Probenecid, also sold under the brand name Probalan, is a medication that increases

uric acid Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the Chemical formula, formula C5H4N4O3. It forms ions and salts known as urates and acid urates, such as ammonium acid urate. Uric acid is a product of the meta ...

excretion in the

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

. It is primarily used in treating

gout Gout ( ) is a form of inflammatory arthritis characterized by recurrent attacks of pain in a red, tender, hot, and Joint effusion, swollen joint, caused by the deposition of needle-like crystals of uric acid known as monosodium urate crysta ...

and

hyperuricemia Hyperuricaemia or hyperuricemia is an abnormally high level of uric acid in the blood. In the pH conditions of body fluid, uric acid exists largely as urate, the ion form. Serum uric acid concentrations greater than 6 mg/dL for females, 7 ...

. 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.

Medical uses

Probenecid is primarily used to treat

and

. Probenecid is sometimes used to increase the concentration of some antibiotics and to protect the kidneys when given with

cidofovir Cidofovir, brand name Vistide, is a topical or injectable antiviral medication primarily used as a treatment for cytomegalovirus (CMV) retinitis (an infection of the retina of the eye) in people with AIDS. Cidofovir was approved for medical ...

. Specifically, a small amount of evidence supports the use of intravenous

cefazolin Cefazolin, also known as cefazoline and cephazolin, is a first-generation cephalosporin antibiotic used for the treatment of a number of bacterial infections. Specifically it is used to treat cellulitis, urinary tract infections, pneumonia, end ...

once rather than three times a day when it is combined with probenecid. It has also found use as a masking agent, 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 In hematology, thrombocytopenia is a condition characterized by abnormally low levels of platelets (also known as thrombocytes) in the blood. Low levels of platelets in turn may lead to prolonged or excessive bleeding. It is the most common coag ...

hemolytic anemia Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular). This most commonl ...

leukemia Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' ...

and

encephalopathy Encephalopathy (; ) means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of overall brain dysfunction; this syndrome ...

are extremely rare. Theoretically probenecid can increase the risk of uric acid

kidney stones Kidney stone disease (known as nephrolithiasis, renal calculus disease, or urolithiasis) is a crystallopathy and occurs when there are too many minerals in the urine and not enough liquid or hydration. This imbalance causes tiny pieces of cr ...

Drug interactions

Some of the important clinical interactions of probenecid include those with

captopril Captopril, sold under the brand name Capoten among others, is an ACE inhibitor, angiotensin-converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of congestive heart failure. Captopril was the first oral ACE inh ...

, indomethacin, ketoprofen,

ketorolac Ketorolac, sold under the brand name Toradol, Acular and Sprix, among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain. Specifically it is recommended for moderate to severe pain. Recommended duration of treatment is l ...

naproxen Naproxen, sold under the brand name Aleve among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain, menstrual cramps, and inflammatory diseases such as rheumatoid arthritis, gout and fever. It is taken orally. It ...

cephalosporins The cephalosporins (sg. ) are a class of β-lactam antibiotics originally derived from the fungus ''Acremonium'', which was previously known as ''Cephalosporium''. Together with cephamycins, they constitute a subgroup of β-lactam antibiotic ...

, quinolones,

penicillins Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from ''Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by '' P. chrysogenum'' ...

methotrexate Methotrexate, formerly known as amethopterin, is a chemotherapy agent and immunosuppressive drug, immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancy, ectopic pregnancies. Types of cancers it is u ...

zidovudine Zidovudine (ZDV), also known as azidothymidine (AZT), was the first antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use in combination with other antiretrovirals. It may be used to prevent mothe ...

, ganciclovir,

lorazepam Lorazepam, sold under the brand name Ativan, Tavor among others, is a benzodiazepine medication. It is used to treat anxiety (including anxiety disorders), insomnia, severe agitation, active seizures including status epilepticus, alcoh ...

, 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.

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, thus reducing blood uric acid levels and reducing its deposition in various tissues. Probenecid also inhibits pannexin 1. Pannexin 1 is involved in the activation of inflammasomes and subsequent release of interleukin-1β causing inflammation. Inhibition of pannexin 1 thus reduces

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

, which is the core pathology of gout.

Pharmacokinetics

In the

kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...

s, probenecid is filtered at the glomerulus, secreted in the

proximal tubule The proximal tubule is the segment of the nephron in kidneys which begins from the renal (tubular) pole of the Bowman's capsule to the beginning of loop of Henle. At this location, the glomerular parietal epithelial cells (PECs) lining bowman’s ...

and reabsorbed in the

distal tubule The distal convoluted tubule (DCT) is a portion of kidney nephron between the loop of Henle and the collecting tubule. Physiology It is partly responsible for the regulation of potassium, sodium, calcium, and pH. On its Apical membrane, apica ...

. 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.

History

During World War II, probenecid was used to extend limited supplies of

penicillin Penicillins (P, PCN or PEN) are a group of beta-lactam antibiotic, β-lactam antibiotics originally obtained from ''Penicillium'' Mold (fungus), moulds, principally ''Penicillium chrysogenum, P. chrysogenum'' and ''Penicillium rubens, P. ru ...

. This use exploited probenecid's interference with drug elimination (via urinary excretion) in the kidneys and allowed lower doses of penicillin to be used. Probenecid was added to the

International Olympic Committee The International Olympic Committee (IOC; , CIO) is the international, non-governmental, sports governing body of the modern Olympic Games. Founded in 1894 by Pierre de Coubertin and Demetrios Vikelas, it is based i ...

's list of banned substances in January 1988, due to its use as a masking agent.

References

{{Antigout preparations Antigout agents World Anti-Doping Agency prohibited substances Benzoic acids