methylamphotericin-b and ornithylamphotericin-methyl-ester

N-D-Ornithyl amphotericin B methyl ester (O-AME), a semisynthetic derivative of amphotericin B methyl ester (AME), was compared with amphotericin B (AMB) and AME. In vitro, O-AME was more active than the other two against Candida spp. and other fungi and was only slightly affected by inoculum size, addition of serum, or changes in pH. In vivo, the dose of O-AME required to produce a 10,000-fold reduction of Candida albicans in a mouse kidney infection was similar to that of AMB and 1/10 that of AME. After intravenous treatment of infected mice and rats and subcutaneous treatment of mice, average 50% protective doses for O-AME and AMB were similar. Acute intravenous 50% lethal doses in mice indicated that O-AME was one-ninth as toxic as AMB but twice as toxic as AME. Acute renal function tests in rats indicated that Sch 28191 was less than 1/10 as toxic as AMB and slightly more toxic than AME. On this basis, the calculated advantage relative to AMB (with AMB equal to 1) was 8 for O-AME and 1.5 for AME.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida albicans; Hydrogen-Ion Concentration; Kidney; Lethal Dose 50; Male; Mice; Microbial Sensitivity Tests; Rats; Rats, Inbred Strains

A high-pressure liquid chromatographic method has been developed for the measurement of N-D-ornithyl amphotericin B methyl ester (Sch 28191) in biological fluid. The method involves protein precipitation with methanol, followed by separation of the supernatant on a reverse-phase column and quantitation by absorbance at 405 nm. This technique resulted in a recovery of 97%. There was a good linear relationship between the peak height ratio and Sch 28191 concentrations ranging from 0.015 to 20 micrograms/ml. In addition, this method was specific for Sch 28191 since all of its analogs tested did not interfere with the assay. The method was reproducible with a lower limit of quantitation of 0.015 microgram/ml. Serum levels obtained from this method were in good agreement with those obtained from a microbiological assay only when drug concentrations were higher than 1.5 microgram/ml. The high-pressure liquid chromatographic method is useful in monitoring serum and urine drug levels in animals and should prove to be useful for pharmacokinetic studies of the drug with therapeutic doses in humans.

Topics: Amphotericin B; Animals; Antifungal Agents; Chromatography, High Pressure Liquid; Dogs; Kinetics