Orally Bioavailable Endochin-Like Quinolone Carbonate Ester Prodrug Reduces Toxoplasma gondii Brain Cysts.
Antimicrob Agents Chemother
; 64(9)2020 08 20.
Article
em En
| MEDLINE
| ID: mdl-32540978
ABSTRACT
Toxoplasmosis is a potentially fatal infection for immunocompromised people and the developing fetus. Current medicines for toxoplasmosis have high rates of adverse effects that interfere with therapeutic and prophylactic regimens. Endochin-like quinolones (ELQs) are potent inhibitors of Toxoplasma gondii proliferation in vitro and in animal models of acute and latent infection. ELQ-316, in particular, was found to be effective orally against acute toxoplasmosis in mice and highly selective for T. gondii cytochrome b over human cytochrome b Despite its oral efficacy, the high crystallinity of ELQ-316 limits oral absorption, plasma concentrations, and therapeutic potential. A carbonate ester prodrug of ELQ-316, ELQ-334, was created to decrease crystallinity and increase oral bioavailability, which resulted in a 6-fold increase in both the maximum plasma concentration (Cmax) and the area under the curve (AUC) of ELQ-316. The increased bioavailability of ELQ-316, when administered as ELQ-334, resulted in efficacy against acute toxoplasmosis greater than that of an equivalent dose of ELQ-316 and had efficacy against latent toxoplasmosis similar to that of ELQ-316 administered intraperitoneally. Treatment with carbonate ester prodrugs is a successful strategy to overcome the limited oral bioavailability of ELQs for the treatment of toxoplasmosis.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Toxoplasma
/
Pró-Fármacos
/
Toxoplasmose Animal
/
Quinolonas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article