Zidovudine with probenecid

Petty BG, Komhauser DM, Lietman PS. Zidovudine with probenecid a warning. Lancet (1990) 1, 1044-5. 

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. 

PROBENECID ZIDOVUDINE t levels of zidovudine with cases of toxicity i hepatic metabolism of zidovudine Avoid co-administration if possible if not possible, l dose of zidovudine... 

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. 

Zidovudine is rapidly absorbed from the G1 tract with peak serum concentrations occurring within 30 to 90 minutes. It binds to plasma proteins to the extent of 35 to 40%. Zidovudine is rapidly metabolized in the liver to the inactive 3 -azido-3 -deoxy-5 -0-beta-D-glucopyranuronosylthymi-dine (GAZT), which has an apparent elimination half-life of 1 hour. Zidovudine undergoes glomerular filtration and active tubular secretion. Coadministration of zidovudine with agents such as dapsone, pentamidine, amphotericin B, flucytosine, vincristine, vinblastine, adriamycin, and interferon with potential to cause nephrotoxicity or cytotoxicity to hematopoietic elements, enhance its risk of adverse effects. Probenecid will inhibit the renal excretion of zidovudine. 

Gaines K, Wong Jung D, Cimoch P, Lavelle J, Pollard R. Pharmacokinetic interactions with oral ganciclovir zidovudine, didanosine, probenecid. 10th Int Conf AIDS, Yokohama (J )an), 1994. Abstract p7. 

In 12 patients with AIDS or AIDS-related complex the eoneurrent use of zidovudine and probenecid 500 mg every 8 hours for 3 days increased the AUC of zidovudine by an average of 80% (range 14 to 192%). ... 

Drugs that may interact with acyclovir include hydantoins, probenecid, theophylline, valproic acid, and zidovudine. 

Ganciclovir interacts with a number of medications, some of which are used to treat HIV or transplant patients. Ganciclovir may cause severe neutropenia when used in combination with zidovudine. Ganciclovir increases serum levels of didanosine, whereas probenecid decreases ganciclovir elimination. Nephrotoxicity may result if other nephrotoxic agents (e.g., amphotericin B, cyclosporine, NSAIDs) are administered in conjunction with ganciclovir. 

In two healthy volunteers, co-administration of probenecid 500 mg every 6 hours altered the pharmacokinetics of a single oral dose of zidovudine 200 mg (46). There was an increase in the average AUC, with a corresponding reduction in oral clearance, attributed to an inhibitory effect of probenecid on the glucuronidation and renal excretion of zidovudine. 

Eight subjects took zidovudine for 3 days with and without probenecid 500 mg every 8 hours for 3 days, and then additional quinine sulfate 260 mg every 8 hours (47). Probenecid increased the AUC of zidovudine by 80%. Quinine prevented the probenecid effect but had no effect on zidovudine kinetics when it was taken without probenecid by four other subjects. All of the effects were secondary to changes in zidovudine metabolism, since neither probenecid nor quinine changed the renal ehmination of zidovudine. 

Severe somnolence and lethargy may occur with combinations of zidovudine and acyclovir. Concomitant cyclosporine enhances nephrotoxicity. Probenecid decreases acyclovir renal clearance and prolongs the plasma t of elimination. Acyclovir may decrease the rerml clearance of other drugs eliminated by active renal secretion (e.g., methotrexate. ... 

Cimoch PJ, Lavelle J, Pollard R, Griffy KG, Wong R, Tarnowsld TL, Casserella S, Jung D. Pharmacokinetics of oral ganciclovir alone and in combination with zidovudine, didanosine, and probenecid in HIV-infected subjects. J Acquir Immune Defic Syndr Hum Retroviral (1998) 17, 227-34. 

Probenecid reduces the loss of zalcitabine and zidovudine, increasing their serum levels. The combination of zalcitabine and probenecid is well tolerated, but the incidence of adverse effects appears to be greatly increased with the combination of probenecid and zidovudine. 

Experimental clinical evidence indicates that probenecid reduces metabolism (glucuronidation) of zidovudine by the liver enzymes, and inhibits renal secretion of the zidovudine glucuronide metabolite. " " The interaction with zalcitabine is presumably due to inhibition of zalcitabine secretion in the renal tubules. ... 

Petty BG, Barditch-Crovo PA, Nerhood L, Komhauser DM, Kuwahara S, Lietman PS. Un-e q)ected clinical toxicity of probenecid (P) widi zidovudine (Z) in patients with HIV infection Intersci Corf Antimicrob Agents Chemoiher ( 99 ) 31, 323. 

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