Probenecid Zidovudine

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... 

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 valganciclovir include didanosine, imipenem-cilastin, nephrotoxic drugs, probenecid, trimethoprim, zalcitabine, and zidovudine. Drugs that may be affected by valganciclovir include cytotoxic drugs, didanosine, and zidovudine. 

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

Drugs that may affect zidovudine include acetaminophen, atovaquone, bone marrow suppressive/cytotoxic agents (eg, adriamycin, dapsone), clarithromycin, doxorubicin, fluconazole, ganciclovir, methadone, nelfinavir/ritonavir, phenytoin, probenecid, ribavirin, rifamycins, stavudine, trimethoprim, and valproic acid. 

WARNING Renal impair is the major tox foUow administration instructions Uses CMV retinitis w/ HIV Action Selective inhibition of viral DNA synth Dose Rx 5 mg/kg IV over 1 h once/wk for 2 wk w/ probenecid Maint 5 mg/kg IV once/2 wk w/ probenecid (2 g PO 3 h prior to cidofovir, then 1 g PO at 2 h 8 h after cidofovir) X in renal impair Caution [C, -] Contra Probenecid or sulfa allergy Disp Inj SE Renal tox, chills, fever, HA, NA /D, thrombocytopenia, neutropenia Interactions t Nephrotox W/ aminoglycosides, amphot icin B, foscar-net, IV pentamidine, NSAIDs, vancomycin t effects W/zidovudine EMS Monitor ECG for hypocalcemia (t QT int val) and hypokalemia (flattened T waves) OD May cause renal failure hydration may be effective in reducing drug levels/effects Cilostazol (Pletal) TAntiplatelet, Arterial Vasodilator/ Phosphodiesterase Inhibitor] Uses Reduce Sxs of intermittent claudication Action Phosphodiesterase in inhibitor t s cAMP in pits blood vessels, vasodilation inhibit pit aggregation Dose 100 mg PO bid, 1/2 h before or 2 h after breakfast dinner Caution [C, +/-] Contra CHE, hemostatic disorders. 

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. 

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. 

Concurrent use of nephrotoxic agents may enhance the potential for nephrotoxicity. Probenecid and cimetidine decrease acyclovir clearance and increase exposure. Somnolence and lethargy may occur in patients receiving zidovudine and acyclovir. 

Drug Interactions Zidovudine Probenecid Imipenem-cilastatin Dapsone Pentamidine Flucytosine Vincristine Vinblastine Adriamycin Amphotericin B TMP-SMX Other nucleoside analogues... 

Uses Herpes simplex zoster Tnfxns Action Interferes w/ viral DNA synth Dose Adults. Dose on IBW if obese >125% IBW PO Initial genital herpes 200 mg PO q4h while awake, 5 caps/d x 10 d or 400 mg PO dd x 7-10 d Chronic suppression 400 mg PO bid Intermittent Rx As inidal Rx, except Rx for 5 d, or 800 mg PO bid, at prodrome Herpes zoster 800 mg PO 5x/d for 7—10 d IV 5—lOmg/kg/dose IV q8h Topical Initial herpes genitalis Apply q3h (6x/d) for 7 d Peds. 5-10 mg/kg/dose IV or PO q8h or 750 mg/m2/24 h + q8h Chickenpox 20 mg/kg/dose PO qid w/ CrCl <50 mL/min Caution [B, +] Contra Hypersensitivity to compound Disp Caps, tabs, susp, inj, oint SE Dizziness, lethargy, confusion, rash, inflammation at IV site Interactions T CNS SE W/ MTX zidovudine, T blood levels H7 probenecid EMS Can cause Szs OD Causes nephrotox which can progress to ARF use fluids w/ caution, symptomatic and supportive... 

Fluconazole, probenecid and atovaquone increase the risk of myelotoxicity by zidovudine. This may be attributed to an increased plasma concentration of zidovudine in the presence of these drugs, perhaps through their inhibitory effects on glucuronose transferase. Rifabutin and rifampin decrease plasma concentrations, and clarithromycin decreases the absorption of zidovudine. Zidovudine and stavu-dine should not be used in combination because they compete for intracellular phosphorylation. 

Wong SL, Van Belle K, Sawchuk RJ (1993) Distributional transport kinetics of zidovudine between plasma and brain extracellular fluid/cerebrospinal fluid in the rabbit— Investigation of the inhibitory effect of probenecid utilizing microdialysis. J Pharmacol Exp Ther 264 899-909. 

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

Wang Y, Wei Y, Sawchuk RJ. Zidovudine transport within the rabbit brain during intracerebroventricular administration and the effect of probenecid. J Pharm Sci 1997 86 1484-90. 

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 reduces the renal tubular secretion of zidovudine (32,33). 

Hedaya MA, Ehnquist WF, Sawchuk RJ. Probenecid inhibits the metabolic and renal clearances of zidovudine (AZT) in human volunteers. Pharm Res 1990 7(4) 411-17. 

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. 

Komhauser DM, Petty BG, Hendrix CW, Woods AS, Nerhood LJ, Bartlett JG, Lietman PS. Probenecid and zidovudine metabolism. Lancet 1989 2(8661) 473-5. 

DC Mays, KF Dixon, A Balboa, LJ Pawluk, MR Bauer, S Nawoot, N Gerber. A nonprimate animal model applicable to zidovudine pharmacokinetics in humans Inhibition of glucuronidation and renal excretion of zidovudine by probenecid in rats. J Pharm Exp Ther 259 1261, 1991. 

On the other hand, probenecid increases the plasma level of acyclovir, allopurinol, barbiturate, benzodiazepines, clof-ibrate, dapsone, dyphylline, methotrexate, NSAIDs, penicillamine, sulfonylureas, and zidovudine. 

Zidovudine, and probably other cytotoxic agents, increase the risk of myelosuppression, as do nephrotoxic agents that impair ganciclovir excretion. Probenecid and... 

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. 

---