Probenecid organic anion transport

Probenecid has been reported to inhibit renal elimination of many drugs acyclovir (325,326), allopurinol (327), bumetanide (328), cephalosporins (329-334), cidofovir (335), ciprofloxacin (336), famotidine (337), fexofenadine (338), furosemide (339), and oseltamivir (Ro 64-0802) (340). Recent studies have elucidated that probenecid is a potent inhibitor of renal organic anion transporters (OAT1 and OAT3) with the Ki values lower than the unbound plasma concentration of probenecid, indicating the interaction with probenecid includes inhibition of the basolateral uptake process mediated by OAT1 and/or OAT3. 

In healthy subjects probenecid completely blocked the renal secretion of the active metabolite of oseltamivir after oral administration, increasing its AUC 2.5 times (20). In vitro studies of the metabolite on the human renal organic anionic transporter I (hOATl) were investigated in Chinese hamster ovary cells stably transfected with the transporter. The metabolite was a low-efficiency substrate for hOATl and a very weak inhibitor of hOATl-mediated transport of pora-aminohippuric acid. Probenecid inhibited the transport of the metabolite, pora-aminohippuric acid, and amoxicillin via hOATl. 

OTA is thought to be transported into the proximal tubular epithelium via organic anion transporters. In primary rabbit proximal tubule cells cultured on microporus supports OTA was taken up from the basolateral compartment and secreted into the apical compartment. This process was sensitive to probenecid [198]. Mouse proximal tubular cells transfected with hOATs (1, 3 and 4) exhibited an enhanced uptake of OTA which was also inhibited by probenecid [199, 200]. However, it is also known that OTA has a high affinity for albumin and it has been demonstrated experimentally that human serum albumin dose depend-ently decreases OTA uptake via hOATl [201]. Whether albumin bound OTA can be transported via megalin mediated endocytosis has not been investigated. 

Probenecid inhibits both kidney binding and toxicity of DCVC Inhibitor of organic anion transport in kidney... 

Probenecid water soluble (Thermo Fisher Scientific), inhibitor of organic anion transporters, prevents leakage of dye to medium. 

Studies with isolated renal brush-border membrane indicate that uptake is a carrier-mediated process, resulting in both transport into intravesicular space and binding to membrane surfaces. The process was saturable with K = 25.1 1.6 pM, and dependent on physiological pH. The inhibition by probenecid and organic anion transport inhibitor—4,4-diiso-thiocyanatos-tilbene-2,2-disulfonic acid (DIDS), 4-acetomido-4-isothiocyanatostilbebe-2,2-disulfonic acid (SITS)— was corroborated. 

Tubular secretion The active secretory systems can rapidly remove the protein-bound drugs from the blood and transport them into tubular fluid as the drugs that are bound to proteins are not readily available for excretion by filtration. The drugs known to be secreted by organic anion secretory system (i.e. strong acids) are salicylates, chlorothiazide, probenecid, penicillin etc. and cation (i.e. bases) includes catecholamines, choline, histamine, hexamethonium, morphine etc. 

Certain molecules, such as p-aminohippuric acid (Fig. 3.18), a metabolite of p-aminobenzoic acid are actively transported from the bloodstream into the tubules by a specific anion transport system. Organic anions and cations appear to be transported by separate transport systems located on the proximal convoluted tubule. Active transport is an energy-requiring process and therefore may be inhibited by metabolic inhibitors, and there may be competitive inhibition between endogenous and foreign compounds. For example, the competitive inhibition of the active excretion of uric acid by compounds such as probenecid may precipitate gout. 

CSF if the meninges are inflamed. Penicillins are organic acids and their rapid clearance from plasma is due to secretion into renal tubular fluid by the anion transport mechanism in the kidney. Renal clearance therefore greatly exceeds the glomerular filtration rate (127 ml/min). The excretion of penicillin can be usefully delayed by concurrently giving probenecid which competes successfully for the transport mechanism. Dosage of penicillins may should be reduced for patients with severely impaired renal function. 

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