Probenecid dosage

Single-dose studies in 6 healthy subjects on the pharmacokinetics of sodium medofenamate 100 mg found that pretreatment with probenecid (dosage unstated) increased its AUC and reduced its apparent plasma clearance by 60%, primarily due to a decrease in non-renal clearance. ... 

Renal impairment - Some degree of renal impairment may be present in patients with gout. A daily dosage of 1 g may be adequate. However, if necessary, the daily dosage may be increased by 0.5 g increments every 4 weeks within tolerance (usually not more than 2 g/day) if symptoms of gouty arthritis are not controlled or the 24 hour urate excretion is not more than 700 mg. Probenecid may not be effective in chronic renal insufficiency, particularly when the glomerular filtration rate is 30 mL/minute or less. 

Penicillin or cephalosporin therapy The PSP excretion test may be used to determine the effectiveness of probenecid in retarding penicillin excretion and maintaining therapeutic levels. The renal clearance of PSP is reduced to about the normal rate when dosage of probenecid is adequate. 

Do not start therapy with probenecid and colchicine until an acute gouty attack has subsided. Flowever, if an acute attack is precipitated during therapy, probenecid and colchicine may be continued without changing the dosage and additional colchicine or other appropriate therapy given to control the acute attack. 

When probenecid (ColBENEMID) is given in sufficient amounts, it will block the active reabsorption of uric acid in the proximal tubules following its glomerular filtration, thereby increasing the amount of urate eliminated. In contrast, low dosages of probenecid appear to compete preferentially with plasma uric acid for the proximal tubule anionic transport system and thereby block its access to this active secretory system. The uricosuric action of probenecid, however, is accounted for by the drug s ability to inhibit the active reabsorption of filtered urate. 

Probenecid can impair the renal active secretion of a variety of acidic compounds, including sulfinpyrazone, sulfonylureas, indomethacin, penicillin, sulfonamides, and 17-ketosteroids. If these agents are to be given concomitantly with probenecid, their dosage should be modified appropriately. Salicylates interfere with the clinical effects of both sulfinpyrazone and probenecid and should be avoided in patients treated with uricosuric agents. Uricosuric agents also can influence the volume of distribution and hepatic metabolism of a number of drugs. 

No formal drug interaction studies of oseltamivir have been performed. Oseltamivir and its carboxylate metabolite do not interact with the cytochrome P450 system. Although probenecid decreases the elimination of oseltamivir, dosage adjustment is not required during coadministration of these drugs because of oseltamivir s margin of safety. Oseltamivir does not interfere with antibody production in response to the influenza vaccine. 

Zidovudine should be used cautiously with any other agent that causes bone marrow suppression, such as interferon-a, trimethoprim-sulfamethoxazole, dap-sone, foscarnet, flucytosine, ganciclovir, and valganci-clovir. Probenecid and interferon-p inhibit the elimination of zidovudine therefore, a dosage reduction of zidovudine is necessary when the drugs are administered concurrently. Ribavirin inhibits the phosphorylation reactions that activate zidovudine, and zidovudine similarly inhibits the activation of stavudine thus, the coadministration of zidovudine with ribavirin or stavudine is contraindicated. 

CMV retinitis in patients with AIDS [in combination with probenecid) IV infusion induction Usual dosage, 5 mg/kgat constant rate over 1 hr onceweeklyfor 2 consecutive wk. Give 2g of PO probenecid 3 hr before cidofovir dose, and then give 1 g 2 hr and 8 hr after completion of the 1 -hr cidofovir infusion (total of 4 g). in addition, give 1 L of 0.9% NaCl over 1-2 hr immediately before the cidofovir infusion, if tolerated, a second liter may be infused over 1 -3 hr at the start of the infusion or immediately afterward. Maintenance 5 mg/kg cidofovir at constant rate over 1 hr once every 2 wk. 

Probenecid is usually started at a dosage of 0.5 g orally daily in divided doses, progressing to 1 g daily after 1 week. Sulfinpyrazone is started at a dosage of 200 mg orally daily, progressing to 400-800 mg daily. It should be given in divided doses with food to reduce adverse gastrointestinal effects. 

When chemotherapeutic mercaptopurines (eg, azathioprine) are given concomitantly with allopurinol, their dosage must be reduced by about 75%. Allopurinol may also increase the effect of cyclophosphamide. Allopurinol inhibits the metabolism of probenecid and oral anticoagulants... 

Intravenous cidofovir is effective for the treatment of CMV retinitis and is used experimentally to treat adenovirus infections. Intravenous cidofovir must be administered with high-dose probenecid (2 g at 3 hours before the infusion and 1 g at 2 and 8 hours after), which blocks active tubular secretion and decreases nephrotoxicity. Cidofovir dosage must be adjusted for alterations in the calculated creatinine clearance or for the presence of urine protein before each infusion, and aggressive adjunctive hydration is required. Initiation of cidofovir therapy is contraindicated in patients with existing renal insufficiency. Direct intravitreal administration of cidofovir is not recommended because of ocular toxicity. 

Excretion The primary route of excretion is through the organic acid (tubular) secretory system of the kidney (see p. 224), as well as by glomerular filtration. Patients with impaired renal function must have dosage regimens adjusted. Thus the Xyz of penicillin G can increase from a normal of 1/2 -1 hour to 10 hours in individuals with renal failure. Probenecid inhibits the secretion of penicillins. Nafcillin is primarily eliminated through the biliary route. [Note This is also the preferential route for the acylureido penicillins in cases of renal failure.]... 

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. 

In low dosages (up to 2 g/day), aspirin reduces urate excretion and blocks the effects of probenecid and other uricosuric agents (116). However, in 11 patients with gout, aspirin 325 mg/day had no effect on the uricosuric action of probenecid (117). In higher dosages (over 5 g/day), salicylates increase urate excretion and inhibit the effects... 

Krogsgaard MR, Hansen BA, Slotsbjerg T, Jensen P. Should probenecid be used to reduce the dicloxacrUin dosage in orthopaedic infections A study of the dicloxacillin-saving effect of probenecid. Pharmacol Toxicol 1994 74(3) 181-4. 

The first compound to arouse interest in the laboratory is the sulfamyl derivative of p-aminobenzoic acid. This was followed by carinamide, which was found to produce high plasma levels of penicillin for long periods of time even when relatively low doses of the antibiotic were administered orally. Probenecid, a structural modification of carinamide, was much more potent on a weight basis and on a dosage basis practical for oral administration. In fact, the combination of penicillin and probenecid was a practical oral formulation and was widely used for the treatment of infections until the costs and availability of penicillin were no longer factors and the better orally active penicillins became available. 

The anaesthetic dosage of thiopental is reduced, and its effects prolonged by pretreatment with aspirin or probenecid. 

A study in patients about to undergo surgery found that pretreatment with aspirin 1 g (given as intravenous lysine acetylsalicylate) one minute before induetion redueed the dosage of thiopental by 34%, from 5.3 to 3.5 mg/kg. Initially thiopental 2 mg/kg was given followed by increments of 25 mg until the eyelash reflex was abolished. The same study also found that oral probenecid 1 g given one hour before anaesthesia reduced the thiopental dosage by 23%, from 5.3 to 4.1 mg/kg. 

Information is limited but what is known shows that the effects of thiopental are increased by aspirin and probenecid. Be alert for the need to reduee the dosage. However, note also that regular aspirin use may ineiease the risk of bleeding during surgery, and it is often recommended that aspirin should not be taken in the week before surgery. ... 

The interaction between indometacin and probenecid is established and adequately documented. Concurrent use should be well monitored because, while clinical improvement can undoubtedly occur, some patients may develop indometacin toxicity (headache, dizziness, light-headedness, nausea, etc.). This is particularly likely in those with some renal impairment. Reduce the indometacin dosage as necessary. Information about other NSAIDs is limited, but these interactions also appear to be established. The clinical importance of most of them is uncertain, but probably small. Reports of adverse effects seem to be lacking, but it would still be prudent to be alert for any evidence of increased adverse effects. Reduce the NSAID dosage if necessary. The exception is ketorolac, which its manufacturers contraindicate with probenecid because of the marked increases seen in its plasma levels. 

---