Toxicity of amphotericin B to analbuminemic rats

Nagase analbuminemic rats (NAR), a strain derived from Sprague Dawley rats (SDR), are suitable to determine the in vivo effect of hyperlipidemia and analbuminemia on the toxicity of the antifungal agent amphotericin B (AB). Cholesterol content was increased in all plasma lipoprotein fractions when SDR serum was compared with NAR serum. Incubation of AB with plasma from animals of both strains and further isolation of plasma lipoprotein by ultracentrifugation, showed that, while in SDR approximately 40% of the injected AB was in the lipoprotein fraction, in NAR almost all (approximately 80%) AB was associated with lipoproteins, especially in the low density lipoprotein fraction. AB spectrophotometry showed differences in the extent of AB aggregation between SDR and NAR plasma fractions. The lack of albumin results in aggregation of the AB present in the infranatant fraction. In vivo, a strong reduction in lethality was observed for NAR when compared to SDR (LD 50% of 6.4 and 1.9 mg/kg respectively). The preferential distribution of AB in the plasma lipoprotein fraction seems to affect pharmacological parameters, with a consequent reduction of toxicity.