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Subchronic toxicity studies of N-D-ornithyl amphotericin B methyl ester in dogs and rats
Abstract:
Two subchronic studies were conducted to assess the potential toxicity of N-D-ornithyl amphotericin B methyl ester (OAME). In both studies the comparative control substance was amphotericin B (AMB). Dogs (5/sex/group) were given OAME (82% pure, based on high-pressure liquid chromatographic (HPLC) analysis) at 0.6, 2.5, and 10 mg/kg or AMB at 0.6 mg/kg intravenously once daily for 3 months. Two dogs per sex per group were retained for a 7-week postdose observation period. Rats (15/sex/group) were given daily doses of OAME at 4, 12, 24, and 36 mg/kg or AMB at 5 and 12 mg/kg intraperitoneally for 3 months. The principal organs of toxicity in both species were the liver, kidneys, and circulating erythrocytes. Hepatic changes in dogs consisted of periportal and centrilobular inflammation in animals of all dosed groups and were equivalent in dogs given 0.6 mg/kg OAME or AMB. In rats, acute hepatic necrosis with periportal, centrilobular, or panlobular distribution in animals of all OAME (except 4 mg/kg) and AMB-dosed groups was observed. These changes were equivalent in the 36-mg/kg OAME- and 12-mg/kg AMB-dosed animals. Renal changes, evidenced by increases in serum urea nitrogen water consumption, urine volume, decreased urine osmolality, and renal tubular changes (ranging from degeneration and regeneration to necrosis), were observed in both species. In dogs, these changes in the OAME-dosed animals were less severe at all doses than those observed in the AMB-dosed dogs. Renal changes in rats, which were mild in comparison to the dogs, were equivalent at doses of 5 and 12 mg/kg AMB and 36 mg/kg OAME. Decreased erythrocyte counts, hematocrit, and hemoglobin values were observed in both species. Unique to the dog study, however, were irreversible behavioral (somnolence, ataxia, tremors, and compulsive searching) and/or morphologic brain changes (gliosis with astrocytic hypertrophy and hyperplasia) at doses of 2.5 and 10 mg/kg OAME. Similar changes were observed in two dogs given 10 mg/kg OAME (100% pure, based on HPLC analysis) in a 6-week pilot study, indicating that the neurological changes were induced by OAME rather than by an impurity. These changes appear related to prolonged exposure to high plasma concentrations of OAME.
Insights
Subchronic toxicity studies revealed N-D-ornithyl amphotericin B methyl ester (OAME) affects the liver, kidneys, and red blood cells in dogs and rats. Dogs also experienced unique neurological changes with OAME exposure.
Area of Science:
- Toxicology
- Pharmacology
- Drug Safety
Background:
- Amphotericin B (AMB) is a potent antifungal agent with known toxicities.
- N-D-ornithyl amphotericin B methyl ester (OAME) is a derivative of AMB investigated for potential therapeutic use.
- Assessing the toxicity profile of novel drug derivatives is crucial for drug development.
Purpose of the Study:
- To evaluate the subchronic toxicity of OAME in comparison to AMB.
- To identify target organs and dose-dependent toxic effects of OAME.
- To investigate potential neurotoxicity associated with OAME administration.
Main Methods:
- Two subchronic studies were conducted in dogs and rats.
- Animals received daily intravenous (dogs) or intraperitoneal (rats) doses of OAME or AMB for 3 months.
- Toxicological endpoints included clinical observations, hematology, clinical chemistry, urinalysis, and histopathology.
Main Results:
- OAME and AMB induced toxicity in the liver, kidneys, and erythrocytes in both species.
- Hepatic necrosis was observed in rats at higher OAME doses and in AMB-treated rats.
- Renal tubular changes and hematological alterations were noted in both species, with dogs showing more severe renal effects from AMB.
- Dogs treated with OAME (2.5 and 10 mg/kg) exhibited irreversible neurological and brain changes, not seen with AMB.
Conclusions:
- OAME exhibits a toxicity profile affecting the liver, kidneys, and erythrocytes, similar to AMB.
- The severity of renal and hepatic toxicity varied between species and drug.
- Unique and irreversible neurotoxicity was observed in dogs treated with OAME, suggesting a specific risk associated with this derivative.