Tissue concentrations and bioactivity of amphotericin B in cancer patients treated with amphotericin B-deoxycholate

Abstract

We have studied amphotericin B concentrations in tissues of 13 cancer patients who died after having received 75 to 1,110 mg (total dose) of amphotericin B-deoxycholate for suspected or proven disseminated fungal infection. Amphotericin B concentrations were measured by high-pressure liquid chromatography (HPLC) and by bioassay, the latter being done on tissue homogenates as well as on tissue methanolic extracts. The fungistatic and fungicidal titers of the tissue homogenates were also tested against three strains of Candida albicans and one strain of Aspergillusfumigatus. Tissue concentrations of amphotericin B measured by HPLC varied with the tested tissues as well as with the total dose of amphotericin B-deoxycholate administered and ranged from 0.4 to 147.1 ,ug/g. A mean of 38.3% (range, 23.0 to 51.3%) of the total dose was recovered by HPLC from all of the tested organs. Bioassay of tissue methanolic extracts reached 58 to 81% of the concentration measured by HPLC, whereas only 15 to 41% was recovered from the homogenates. Overall, 27.5% of the total dose was recovered from the liver, 5.2% was recovered from the spleen, 3.2% was recovered from the lungs, and 1.5% was recovered from the kidneys. The median concentration in bile was 7.3 ,ug/ml, suggesting that biliary excretion could contribute to amphotericin B elimination to an estimated range of 0.8 to 14.6% of the daily dose. Fungicidal titers were seldom measured in tissues, but fungistatic titers were observed and were linearly correlated with amphotericin B concentration measured by HPLC. In conclusion, only a small proportion of the amphotericin B administered as amphotericin B-deoxycholate to patients seems diffusible and bioactive.Amphotericin B remains the therapy of choice for invasive fungal infections in immunocompromised patients (2, 8), but treatment failures are still numerous, especially in patients with severe and persisting neutropenia (9,16). Despite the widespread use of amphotericin B during the last 30 years, the pharmacokihetic profile of this agent in humans remains unclear. Concentrations of amphotericin B in serum measured after the administration of conventional doses (0.4 to 1 mg/kg per day) range from 0.5 to 2 ,ug/ml and usually exceed

Amphotericin B Is Cytotoxic at Locally Delivered Concentrations

“…This concentration is below the lowest level that produced toxicity in our study and far below the lethal levels in our study but may not represent the tissue concentration adjacent to the local depot. Collette et al [3] reported tissue concentrations of amphotericin B from intravenous infusion assessed with high-performance liquid chromatography of as high as 147 lg/g. The authors observed a correlation between increased amphotericin B delivery and increased fungistatic and fungicidal titer; however, the local toxicity of the amphotericin B was not evaluated as samples were taken from deceased subjects.…”

Central nervous system aspergillosis in allogeneic stem cell transplant recipients

“…29,30 Amphotericin B, the standard therapy for aspergillosis, as well as itraconazole both have poor penetrance into the CNS. [31][32][33] Voriconazole has better penetrance 28 and may thus become the therapy of choice in patients with CNS aspergillosis. Recently, voriconazole has been found superior to amphotericin B in the primary treatment of invasive aspergillosis.…”

Successful treatment of cerebral aspergillosis with a novel triazole (voriconazole) in a patient with acute leukaemia

“…So far, no unequivocal advantage has been proved for any one type of drug therapy, neurosurgical procedure or combined treatment approach (Coleman et al, 1995). Itraconazole and amphotericin B, either as desoxycholate or encapsuled in liposomes, poorly penetrate across the brain-blood barrier (Como & Dismukes, 1994;Collette et al, 1989Collette et al, , 1991. Flucytosine may be recovered in high concentrations from the CSF, but aspergilli frequently show resistance to this drug (Francis & Walsh, 1992).…”