The History and Future of Probenecid

Abstract

Probenecid was initially developed with the goal of reducing the renal excretion of antibiotics, specifically penicillin. It is still used for its uricosuric properties in the treatment in gout, but its clinical relevance has sharply fallen and is rarely used today for either. Interestingly, throughout the last 60 years, there have been a host of apparently unrelated studies using probenecid in the clinical and basic research arena, including its potential use in the diagnosis and treatment of depression and its use to prevent fura-2 leakage in calcium transient studies. Recently, it has been shown that it is also an agonist of the Transient Receptor Potential Vanilloid 2 channel. Due to its unique action and new findings implicating TRPV channels in physiology and in disease, probenecid may have a new future as a research tool, and perhaps as a clinical agent in the neurology and cardiology fields. We review the history of probenecid in this paper and its potential future uses.

Probenecid Improves Cardiac Function in Patients With Heart Failure With Reduced Ejection Fraction In Vivo and Cardiomyocyte Calcium Sensitivity In Vitro

“…Since that time, probenecid has been safely used as adjuvant therapy for other antibiotics,35 antivirals,22 and early antidepressants,36 as well as for the prevention of gout 14. The use of probenecid in patients has decreased in recent years as other therapeutic options for gout have emerged, though it is still actively used in basic science laboratories as a Fura‐2 blocker 37…”

“…Several vanilloid subtypes have been shown to be important mediators of vascular tone, cerebral blood flow, neointimal hyperplasia, and pulmonary hypertension 11, 12, 13. Expression of the transient receptor potential vanilloid 2 (TRPV2) channel was noted in abundance in murine myocardial tissue, specifically in the left ventricle 14. Iwata et al initially described that cardiac‐specific overexpression of TRPV2 resulted in chamber dilation of all cavities of the murine heart,15 while our laboratory recently demonstrated increased expression of TRPV2 in diseased hearts 16.…”

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

“…Some DDIs, such as penicillin and probenecid, are well established and have been put to clinical use; the half-life of penicillin is greatly prolonged by coadministration of probenecid, an OAT inhibitor (45)(46)(47). In contrast, some DDIs can lead to dire consequences.…”

Transporters and Drug-Drug Interactions: Important Determinants of Drug Disposition and Effects

“…The drug was initially used to decrease the renal tubular secretion of antibiotics, especially benzylpenicillin, to prolong their elimination half-life and increase serum concentrations (Burnell and Kirby, 1951). The need to raise serum concentrations of benzylpenicillin was mainly attributable to limited supplies of antibiotics during and shortly after World War II (Robbins et al, 2012). Because of its uricosuric properties mediated by inhibition of renal tubular reabsorption of urate, probenecid was also standard of care for prevention of gout symptoms in predisposed patients (Robbins et al, 2012).…”