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Toxicokinetics
Published in Frank A. Barile, Barile’s Clinical Toxicology, 2019
Other organic ions undergo active tubular secretion. Organic anion transporter proteins (oat, organic acid transporters) and organic cation transporter proteins (oct, organic base transporters) both actively secrete polar molecules from capillaries to the PCT lumen. Some classic examples include the active tubular secretion of para-aminohippuric acid (PAH) by oat proteins, as well as sulfonamide antibiotics and methotrexate, which compete for the same secretory pathways. Probenecid, a uricosuric agent used in the treatment of gout, competes for oat proteins as part of its therapeutic mechanism. While small doses of the drug actually depress the excretion of uric acid by interfering with tubular secretion but not reabsorption, larger doses depress the reabsorption of uric acid and lead to increased excretion and a fall in serum levels. Similarly, small doses of probenecid decrease the renal excretion of penicillins, which compete for the same oat proteins, necessitating an adjustment of the antibiotic dosage regimen.
Formulary
Published in Sarah Bekaert, Alison White, Integrated Contraceptive and Sexual Healthcare, 2018
Sarah Bekaert, Alison White, Kathy French, Kevin Miles
Probenecid works on the kidneys to increase the rate at which uric acid is excreted. In gout, crystals of uric acid form in the joints and cause the characteristic pain and inflammation. By lowering the levels of uric acid, gout can be prevented. Although probenecid increases the rate of removal of uric acid in the urine, it actually decreases the rate of removal of certain other medicines, e.g. some antibiotics. This effect has been used to increase the levels of some antibiotics in the body. For example, probenecid is used along with penicillin antibiotics to increase antibiotic blood levels. This increase makes the antibiotic more effective in treating certain infections.
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Published in Caroline Ashley, Aileen Dunleavy, John Cunningham, The Renal Drug Handbook, 2018
Caroline Ashley, Aileen Dunleavy, John Cunningham
Amoxicillin is metabolised to a limited extent to penicilloic acid which is excreted in the urine. About 60% of an oral dose of amoxicillin is excreted unchanged in the urine by glomerular filtration and tubular secretion. Probenecid reduces renal excretion. High concentrations have been reported in bile; some may be excreted in the faeces.
Advances in pharmacotherapies for hyperuricemia
Published in Expert Opinion on Pharmacotherapy, 2023
Federica Piani, Davide Agnoletti, Claudio Borghi
Probenecid is a benzoic acid derivative initially developed to decrease the renal excretion of penicillin. Probenecid inhibits URAT1, OAT1, and OAT3 transporters, the ATP release channel pannexin 1, and, interestingly, has also modulatory activity against TRPV2, an ionic channel involved in the pathogenesis of heart failure [65]. Probenecid has been in clinical use for more than 50 years and has shown a limited adverse effect profile, with side effects similar to those of allopurinol (skin rash, gastrointestinal complaints, hypersensitivity). The recommended dosage goes from 500 mg to 1 g once daily. After oral administration, it is completely absorbed, and its half-life goes from 4 to 12 h. Probenecid is metabolized in the liver, and its metabolites are highly bound to plasma protein and eliminated by renal excretion [32]. Common side effects are indirect and involve drug-to-drug interactions. In fact, probenecid decreases renal elimination, thus increasing the concentration, of several commonly used drugs such as antibiotics. In moderate-to-severe chronic kidney disease (eGFR under 50 ml/min) there is a loss of effect, thus probenecid should be avoided [66]. In Dutch trials, patients refractory to allopurinol showed a higher response rate to benzbromarone than to probecencid (92% vs. 65%) [60].
Uric acid as a cardiorenal mediator: pathogenesis and mechanistic insights
Published in Expert Review of Cardiovascular Therapy, 2021
Asma Gulab, Ricardo Torres, Jerald Pelayo, Kevin Bryan Lo, Anum Shahzad, Supriya Pradhan, Janani Rangaswami
A large cohort study involving 38,888 gout patients aged 65 years and older (enrolled in Medicare from 2008 to 2013) found that probenecid compared with allopurinol was associated with significantly decreased risk of MI, stroke and heart failure exacerbation [62]. In line with this, more large-scale, long-term studies are required to better evaluate whether probenecid can be safely administered chronically to patients with heart failure with reduced ejection fraction to improve symptoms and outcomes such as mortality and/or rehospitalization. It is worth mentioning that the use of Probenecid is limited by GFR, its use is to be avoided in patients with GFR<30 ml/min. Another agent Lesinurad, a selective Uric acid reabsorption inhibitor has been shown to achieve target serum uric acid levels in an increased proportion of patients when use in conjunction with Allopurinol as compared to Allopurinol alone however no long term studies are available yet to see the effect on cardiovascular outcomes [63]. Whether this seemingly observed advantage of the use of uricosuric agents over XO inhibitors is related to net diuresis and volume control among heart failure patients is yet to be determined.
Investigational drugs in early phase clinical trials targeting thermotransient receptor potential (thermoTRP) channels
Published in Expert Opinion on Investigational Drugs, 2020
Asia Fernández-Carvajal, Rosario González-Muñiz, Gregorio Fernández-Ballester, Antonio Ferrer-Montiel
Despite the potential therapeutic interest of TRPV2 modulation, thus far, only two-channel modulators have shown promising pharmacological results, namely Probenecid and Tranilast as activator and inhibitor respectively (Table 1). Probenecid acts as a TRPV2 agonist and has recently become the subject of study as an investigational therapy for the treatment of cardiomyopathy due to its positive inotropic effects. Probenecid is an FDA approved drug for the treatment of gout and hyperuricemia and has been used safely in humans for decades for different indications. A Phase II clinical assay (NCT01814319) has shown that Probenecid improves cardiac function in patients with heart failure with no significant adverse effects after 1-week treatment. This therapeutic action is presumably exerted through TRPV2 activation [99]. Studies evaluating long-term safety are needed to become a new therapeutic option for patients with heart failure. A Phase IV clinical assay (NCT03965351) is ongoing to determine if Probenecid improves magnetic resonance (MRI) parameters of systolic and/or diastolic dysfunction as well as associated symptoms in patients with a Fontan circulation.