Probenecid Methotrexate

PROBENECID METHOTREXATE T methotrexate levels Probenecid 1 elimination of methotrexate renally by interfering with tubular secretion in the proximal tubule and also l protein binding of methotrexate (a relatively minor effect). Probenecid competes with methotrexate for renal elimination Avoid co-administration if possible if not possible, 1 dose of methotrexate and monitor FBC closely... 

The co-administration of drugs which inhibit the transporters involved in renal tubular secretion can reduce the urinaty excretion of drugs which are substrates of the transporter, leading to elevated plasma concentrations of the drugs. For example, probenecid increases the plasma concentration and the duration of effect of penicillin by inhibiting its renal tubular secretion. It also elevates the plasma concentration of methotrexate by the same mechanism, provoking its toxic effects. 

If the unbound drug concentrations in plasma are higher than their K values on the transporters, then transporter function may be significantly affected [106], Following a pharmacokinetic analysis of the effect of probenecid on the hepatobiliary excretion of methotrexate, it has been shown the extent of an in vivo drug-drug interaction can be quantitatively predicted from the kinetic parameters for transport across the sinusoidal and bile canalicular membranes determined in vitro [107]. 

Ueda, K., Kato, Y., Komatsu, K., Sugiyama, Y., Inhibition of biliary excretion of methotrexate by probenecid in rats quantitative prediction of interaction from in vitro data, J. Pharmacol. Exp. Ther. 2001,... 

Drugs that may be affected by aspirin include ACE inhibitors, acetazolamide, anticoagulants, anticonvulsants (hydantoins, valproic acid), beta blockers, diuretics, methotrexate, NSAIDs, oral hypoglycemics, and uricosuric agents (probenecid, sulfinpyrazone). 

Drugs that may affect aspirin include activated charcoal, ammonium chloride, ascorbic acid or methionine, antacids and urinary alkalinizers, carbonic anhydrase inhibitors, corticosteroids, and nizatidine. Drugs that may be affected by aspirin include alcohol, ACE inhibitors, anticoagulants (oral), beta-adrenergic blockers, heparin, loop diuretics, methotrexate, nitroglycerin, NSAIDs, probenecid and sulfinpyrazone, spironolactone, sulfonylureas and exogenous insulin, and valproic acid. 

Drugs that may be affected by probenecid include acyclovir allopurinol barbiturates benzodiazepines clofibrate dapsone dyphylline methotrexate NSAIDs pantothenic acid penicillamine rifampin sulfonamides sulfonylureas zidovudine salicylates. 

Drugs that may affect methotrexate include oral aminoglycosides, charcoal, chloramphenicol, folic acid, NSAIDs, PCNs, probenecid, salicylates, sulfonamides, TCN, trimethoprim. 

Salicylates, probenecid, and sulfonamides inhibit the renal tubular secretion of methotrexate and may displace it from plasma proteins. Asparaginase inhibits protein synthesis and may protect cells from methotrexate cytotoxicity by delaying progression from Gj-phase to S-phase. Methotrexate may either enhance or inhibit the action of fluorouracil, depending on its sequence of administration. 

Methotrexate Aspirin, phenylbutazone, probenecid Delayed excretion Increased toxicity. 

Bourke RS, Chheda G, Bremer A, et al. Inhibition of renal tubular transport of methotrexate by probenecid. Cancer Res 1975 35 110-116. 

P-Lactam antibiotics Cephalosporins Cidofovir Furosemide Ganciclovir Methotrexate NSAIDs Probenecid Tetracycline Zidovudine KW-3902 ... 

For a displacement interaction to become clinically important, a second mechanism usually operates sodium valproate can cause phenytoin toxicity because it both displaces phenytoin from its binding site on plasma albumin and inhibits its metabolism. Similarly aspirin and probenecid (and possibly other nonsteroidal anti-inflammatory drugs) displace the folic acid antagonist methotrexate from its protein-binding site and reduce its rate of active secretion by the renal tubules the result is serious methotrexate toxicity. 

Interference with active transport. Organic acids are passed from the blood into the urine by active transport across the renal tubular epithelium. Penicillin is mostly excreted in this way. Probenecid, an organic acid that competes successfully with penicillin for this transport system, may be used to prolong the action of penicillin when repeated administration is impracticable, e.g. in sexually transmitted diseases, where compliance is notoriously poor. Interference with renal excretion of methotrexate by aspirin, of zidovudine by probenecid and of digoxin by quinidine, contribute to the potentially harmful interactions with these combinations. 

Probenecid competes with methotrexate for renal tubular secretion, and can cause severe hematological toxicity. 

Severe pancytopenia occurred in an elderly patient taking low-dose methotrexate and probenecid (144). 

Probenecid reduces the renal tubular secretion of methotrexate, enhancing its effect (29) and may reduce its plasma protein binding (30). 

Concomitant use of heparin and oral anticoagulants can increase the risk for bleeding due to the antiplatelet effect of aspirin. In addition, use with alcohol can increase the risk of Gl bleeding. / spirin displaces a number of drugs (e.g., tolbutamide, nonsteroidal anti-inflammatory drugs [NSAIDs], methotrexate, phenytoin, and probenecid) from protein binding sites in the blood. Corticosteroid use can reduce serum salicylate levels by increasing the clearance of aspirin. 

Clinically important, potentially hazardous interactions with aspirin, methotrexate, probenecid... 

Methotrexate Probenecid p-Aminohippurate (PAH) Glucuronic acid conjugates Sulphate conjugates N4 -Acetylated sulphonamides Cimetidine... 

Aherne, G.W., Piall, E., Marks, V. et al. (1978) Prolongation and enhancement of serum methotrexate concentrations by probenecid. British Medical Journal, 1, 1097-1099. 

Altered excretion Competition for transport systems in kidney Elimination of methotrexate (cancer chemotherapy) inhibited by probenecid (for gout)... 

MRP2 (ABCC2) Liver, kidney, intestine Apical doxorubicin, vincristine, estradiol-17-p-D-glucuronide Methotrexate, vinblastine. indomethacin, probenecid, sulfinpryazone, PSC933. LY475776 MK571, furosemide. 

OAT2 (SLC22A7) Kidney, Basolateral PAH, salicylate, methotrexate. Probenecid,... 

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