Probenecid Cidofovir

OATl (SLC22A6) Probenecid Cidofovir Decrease renal CL by 27%, which is sufficient to reduce cidovovir nephrotoxicity Inhibition of renal proximal tubular basolateral OATl... 

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. 

Cidofovir has extremely low oral bioavailability and so must be administered intravenously. Although the plasma elimination half-life averages 2.6 hours, the diphosphate form of the drug is retained within host cells and has an intracellular half life of 17 to 65 hours. A phosphocholine metabolite has a half-life of approximately 87 hours and may serve as an intracellular reservoir of the drug. Cidofovir is not significantly metabolized and is excreted unchanged by the kidney. Glomerular filtration and probenecid-sensitive tubular secretion are responsible for cidofovir elimination. 

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. 

Complete the full course of probenecid with each dose of cidofovir... 

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. 

Antiviral Efficacy and Clinical Use. Cidofovir (Vis-tide) is used primarily to treat CMV retinitis in people with AIDS.111 When used clinically, this drug is often combined with probenecid, an agent that inhibits renal excretion of cidofovir, thereby providing higher plasma levels of this antiviral agent.112... 

Wolf DL, Rodriguez CA, Mucci M, et al. Pharmacokinetics and renal effects of cidofovir with a reduced dose of probenecid in HIV-infected patients with cytomegalovirus retinitis. J Clin Pharmacol. 2003 43 43-51. 

Although the terminal half-life of cidofovir is about 2.6 hours, the active metabolite, cidofovir diphosphate, has a prolonged intracellular half-life of 17-65 hours, thus allowing widely spaced administration. A separate metabolite, cidofovir phosphocholine, has a half-life of at least 87 hours and may serve as an intracellular reservoir of active drug. Peak serum concentrations when administered with probenecid (see Clinical Uses) are about 19 g/mL. Cerebrospinal fluid penetration is poor after intravenous administration. Elimination involves active renal tubular secretion. High-flux hemodialysis has been shown to reduce the serum levels of cidofovir by approximately 75%. 

The primary adverse effect of intravenous cidofovir is a dose-dependent nephrotoxicity. Concurrent administration of other potentially nephrotoxic agents (eg, amphotericin B, aminoglycosides, nonsteroidal anti-inflammatory drugs, pentamidine, foscarnet) should be avoided. Prior administration of foscarnet may increase the risk of nephrotoxicity. Other potential side effects include uveitis, decreased intraocular pressure, and probenecid-related hypersensitivity reactions. Neutropenia and metabolic acidosis are rare. The drug caused mammary adenocarcinomas in rats and is embryotoxic. 

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. 

Second, certain nucleotide phosphonates (e.g., adefovir and cidofovir) are effective antivirals, but their use in the clinic is limited by renal toxicity. This is believed to be caused by avid uptake at the basolateral membrane of renal proximal tubule cells followed by slow transport into the urine at the apical membrane, a sequence of events that results in intracellular drug accumulation and thus toxicity. As with penicillin, the OAT family of transporters has been implicated in cidofovir uptake. Co-administration of probenecid with cidofovir has been shown to decrease renal clearance of the antiviral and reduce its nephrotoxicity, presumably through com-... 

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

Lacy SA, Hitchcock MJM, Lee WA, Tellier P, Gundy KC. Effect of oral probenecid coadministration on the chronic toxicity and pharmacokinetics of intravenous cidofovir in cynomolgus monkeys. Toxicol Sci 1998 44 97-106. 

Ind avenous cidofovir is well tolerated. The major deatment-limidng toxicity of this drug is irreversible nephrotoxicity (Plosker and Noble, 1999). Ind avenous pre-hydradon with normal saline and aclminisdadon of oral probenecid must be used with each cidofovir infusion to lessen the effects on the kidney. Serum creadnine and urine protein must be monitored with each infusion and adjusted accordingly. Other adverse effects associated with its use are neudopenia and peripheral neuropathy (Plosker and Noble, 1999). 

Two cases of iritis shortly after intravenous administration of cidofovir have been reported (4). Intravitreal administration of cidofovir delays the progression of CMV retinitis, but can be associated with reduced intraocular pressure or vitreitis (5). In two cases the drug association with the iritis was demonstrated by withdrawal and rechaUenge (6). These patients had also taken probenecid, but it is not clear whether or not that was involved. The evidence is that in such cases the cidofovir should be withdrawn treatment should be with a mydriatic and glucocorticoids. 

Cidofovir 5 mg/kg weekly X 2 (induction) 5 mg/kg every 2 wk 90% 100% No data avoid No data avoid Dose-limiting nephrotoxicity with proteinuria, glycosuria, renal insufficiency nephrotoxicity and renal clearance reduced with coadministration of probenecid No data avoid No data avoid No data avoid... 

At cidofovir doses of 3 mg/kg, probenecid does not appear to affect cidofovir pharmacokinetics, while at higher doses, tubular secretion and renal clearance of cidofovir are reduced [30]. 

Berns J. Hemolytic uremic syndrome and thrombotic thrombocytopenic purpura associated with HIV infection. In Renal and Urologic Aspects of HIV Infection. Kimmel PL, Berns JS (editors). Churchill Livingstone, Inc, Philadelphia, PA 1995 p. 111-133. Lacy SA, Hitchcock MJ, Lee WA, Tellier P, Cundy KC. Effect of oral probenecid coadministration on the chronic toxicity and pharmacokinetics of intravenous cidofovir in cynomolgus monkeys. Toxicol Sci 1998 44 97-106. 

OAT Penicillin Methotrexate Cidofovir Furosemide Various Probenecid NSAIDS Probenecid Probenecid Uremic Toxins f duration of action of penicillin f plasma exposure of methotrexate leading to toxicity J, kidney accumulation and lower incidence of cidofovir nephrotoxicity J, diuretic activity of furosemide J, excretion of OAT substrates... 

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