Intravenous and Subcutaneous Toxicity and Absorption Kinetics in Mice and Dogs of the Antileishmanial Triterpene Saponin PX-6518

Abstract

The intravenous (IV) and subcutaneous (SC) toxicity and absorption kinetics of the antileishmanial triterpene saponin PX-6518 and its active constituents maesabalide-III and -IV were studied in mice and dogs. A high-dose wash-out study of PX-6518 at 20 mg/kg SC for 5 days and a single low-dose wash-out study at 1, 2.5 or 5 mg/kg SC and IV with follow-up until day 35 after treatment were performed in mice. Beagle dogs received three escalating doses of maesabalide-III and -IV at weekly intervals (0.01, 0.1 and 0.5 mg/kg IV and maesabalide-III was also dosed SC at 0.1, 0.2 and 0.4 mg/kg). Endpoint measurements included clinical, hematological and serum biochemical parameters. Pathology and toxicokinetic studies were performed on the dogs. Whereas the neutrophils and aspartate aminotransferase and alanine aminotransferase levels were increased in the high-dose wash-out mouse study, these parameters did not change in the low-dose wash-out study. The dogs were far more susceptible than mice to liver toxicity (hepatocellular necrosis and elevated liver enzymes) and developed a painful inflammatory reaction at the SC injection site. Toxicokinetic analysis revealed a non dose-linear systemic availability with plasma concentrations above the antileishmanial IC50 after only a single dose at 0.01 mg/kg IV or 0.1 mg/kg SC. Related to the long half-life (T1/2 71–91 h after SC dosing), repeated dosing at weekly intervals may result in drug accumulation and enhanced toxicity. It was decided not to pursue further drug development for PX-6518 because of the hepatotoxic risk.

Glycosylated Triterpenoids as Endosomal Escape Enhancers in Targeted Tumor Therapies

“…In vivo, the applied dose must be below the critical hemolytic concentration since otherwise progressive hemolysis will lead to death. Investigations on the toxic effects of an anti-leishmanial triterpene saponin showed that the target toxicity parameters leukocytosis, granulocytosis, lymphopenia, and the strong increase of the liver enzymes alkaline phosphatase, aspartate, and alanine aminotransferase did not return to normal pre-dose values within four weeks after subcutaneous dosing of 20 mg/kg for five consecutive days, but when injecting 5 mg/kg, the effects were marginal and doses of 2.5 mg/kg or lower did not differ from vehicle-treated control [ 139 ]. Subcutaneous injections of a saponin composite from Gypsophila species with endosomal escape enhancer properties showed toxic effects at 5 mg/kg and were lethal at 10 mg/kg, however, the typical dose of 0.75 to 1.5 mg/kg that is used for a combination therapy of saponins with targeted toxins is not toxic [ 140 ].…”

Transaminase enzymes and lipid profiles and histological changes in Wistar rats after administration of bintangur (Calophyllum soulattri) leaves ethanolic extract

“…Several other plants containing saponins have been shown to be hepatotoxic and increased ALT and AST serum level. Saponin also caused hemolysis and lower cell surface pressure, lead damage to heart muscle tissues cell (Maes 2013). Besides, saponin decreased cholesterol and triglycerides serum level; it inhibited absorption of cholesterol and pancreatic lipoprotein lipase (Kamesh 2012).…”