Amphotericin excretion

Hypomagnesemia is usually associated with disorders of the intestinal tract or kidneys. Drugs (e.g., aminoglycosides, amphotericin B, cyclosporine, diuretics, digitalis, cisplatin) or conditions that interfere with intestinal absorption or increase renal excretion of magnesium can cause hypomagnesemia. 

Metabolism/Excretion — Amphotericin B has a relatively short initial serum half-life of 24 hours, followed by a second elimination phase with a half-life of approximately 15 days. The drug is slowly excreted by the kidneys with 2% to 5% as the biologically active form. 

Lactation It is not known whether amphotericin B is excreted in breast milk however, consider discontinuing nursing. 

The major route of elimination of amphotericin B is by metabolism, with little intact drug detected in urine or bile. About 5% of amphotericin B is excreted in the urine as active drug, with drug still detectable in the urine 7 or more weeks after the last dose. Serum levels... 

Flucytosine Interferes with DNA and RNA synthesis selectively in fungi Synergistic with amphotericin systemic toxicity in host due to DNA and RNA effects Cryptococcus and chromoblastomycosis infections Oral duration, hours renal excretion Toxicity Myelosuppression... 

Amphotericin B is available in the form of sterile lyophilized powder. Because it is insoluble in water, it is marketed with sodium deoxycholate for dispersal in sterile water and 5% dextrose. The polyene antibiotics — amphotericin B, nystatin, and candicidin — are all poorly absorbed from the gastrointestinal tract. In the plasma, amphotericin B binds to lipoproteins including cholesterol. It is extensively metabolized and the inactive metabolite, or metabolites, are slowly excreted in the urine. 

Flucytosine (Ancobon) possesses clinically useful activity against Cryptococcus neoformans, Candida species, Torulopsis glabrata, and the agents of chromomycosis. Susceptible fungi deam-inate flucytosine to 5-fluorouracil, which becomes an antimetabolite. Flucytosine, which is excreted by the kidney, should be used cautiously in the setting of renal impairment. Flucytosine is a bone marrow depressant. Flucytosine is used in combination with amphotericin B. 

Nystatin [nye STAT in] is a polyene antibiotic its structure, chemistry, mode of action, and resistance resemble those of amphotericin B. Its use is restricted to topical treatment of Candida infections because of its systemic toxicity. The drug is negligibly absorbed from the gastrointestinal tract, and it is never used par-enterally. It is administered as an oral agent ( swish and swallow ) for the treatment of oral candidiasis. Excretion in the feces is nearly quantitative. Adverse effects are rare because of its lack of absorption, but occasionally nausea and vomiting occur. 

AMPHOTERICIN ANTI FUNG ALS -FLUCYTOSINE t flucytosine levels, with risk of toxic effects Amphotericin causes 1 renal excretion of flucytosine and t cellular uptake The combination of flucytosine and amphotericin may be used therapeutically. Watch for early features of flucytosine toxicity (gastrointestinal upset) monitor renal and liver function closely... 

AMPHOTERICIN ADEFOVIR DIPIVOXIL Possible T efficacy and side-effects Competition for renal excretion Monitor renal function weekly... 

ADEFOVIR DIPIVOXIL 1. ANTIBIOTICS -aminoglycosides, vancomycin 2. ANTICANCER AND IMMUNOMODULATING DRUGS - cidosporin, tacrolimus 3. ANTIFUNGALS-amphotericin, 4. ANTIPROTOZOALS-pentamidine 5. ANTIVIRALS - cidofovir, foscarnet sodium, tenofovir Possible t efficacy and side-effects Competition for renal excretion Monitor renal function weekly... 

Flucytosine (5-fluorocytosine) is metabolised in the fungal cell to 5-fluorouracil which inhibits nucleic acid synthesis. It is weU absorbed from the gut, penetrates effectively into tissues and almost all is excreted unchanged in the urine (t) 4 h). The dose should be reduced for patients with impaired renal function, and the plasma concentration should be monitored. The drug is well tolerated when renal function is normal. Candida albicans rapidly becomes resistant to flucytosine which ought not to be used alone it may be combined with amphotericin (see Table 14.2) but this increases the risk of adverse effects (leucopenia, thrombocytopenia, enterocolitis) and it is reserved for serious infections where the risk-benefit balance is favourable (e.g. Cryptococcus neoformans meningitis). 

Based on its considerable nephrotoxic potential, cisplatin should be given after, rather than before, other anticancer drugs and other drugs with a low therapeutic index (for example aminoglycoside antibiotics or bleomycin) that are primarily excreted in the urine in unchanged form. Concomitant use of potentially nephrotoxic agents (for example conventional amphotericin, tacrohmus) with cis-platin should be avoided (279,280). 

Major functions of the distal nephron include the regeneration of bicarbonate, the excretion of acid (hydrogen ion), the secretion of potassium, and the reabsorption of water. Damage to this portion of the nephron may present as significant acidemia and either hypo-or hyperkalemia, depending on the mechanism of injury. For example, amphotericin B produces small pores in the luminal membrane of distal tubular cells. These pores allow small molecules such as potassium to leak out the molecules are then wasted in the urine. Consequently, amphotericin B nephrotoxicity is characterized by hypokalemia secondary to renal potassium wasting. ATN is associated with urinary sediment characterized by the presence of tubular cells, coarse granular casts, and rarely, RBC casts. 

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. 

ABSORPTION, DISTRIBUTION, AND EXCRETION Gastrointestinal (Gl) absorption of amphotericin B is negligible and intravenous dehvery is used. Amphotericin B in plasma is >90% bound to proteins. Drag elimination apparently is unchanged in anephiic patients and those on hemodialysis. Hepatic or biliary disease has no known effect on drag metabolism in humans. The terminal phase of elimination has a tj, of 15 days. Concentrations of amphotericin B in fluids from inflamed pleura, peritoneum, synovium, and aqueous humor are approximately two-thirds of plasma trough concentrations. Little amphotericin B penetrates into cerebrospinal fluid (CSF), vitreous humor, or amniotic fluid. 

Ciassification and pharmacokinetics Amphotericin B is a polyene antibiotic related to nystatin. Amphotericin is poorly absorbed from the gastrointestinal tract and is usually administered intravenously as a colloidal suspension, or in some cases in a lipid formulation. The drug is widely distributed to all tissues except the CNS. Elimination is mainly via slow hepatic metabolism the half-life is approximately 2 weeks. A small fraction of the drug is excreted in the urine, dosage modification is necessary only in extreme renal dysfunction. Amphotericin B is not dialyzable. 

Significant reduction in serum cholesterol levels can also be demonstrated in animals simultaneously fed polyenes and high sterol diets. Dogs appeared more able to maintain their serum cholesterol levels when fed sterols and filipin, amphotericin B or candicidin [145,535] but nystatin had no effect. The anti-hypercholesterolemic effect was not simply due to the prevention of sterol uptake [538,539]. A consequence of the excretion of sterol-polyene complexes in the faeces is the loss of bile salts (which are steroids) and this tends to remove sterol from the body. This resulted in increased hepatic synthesis, increased utilization of adipose fat and reduced sebum levels. Candicidin has been suggested as an antihypercholesterolemic agent in man [546]. 

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