In vitro biotransformation, in vivo efficacy and pharmacokinetics of antimalarial chalcones
| Autor: | Lisa Xie, Constance O. Asher, ThuLan Luong, Qigui Li, Daniel A. Nichols, Clare E. Gutteridge, Gettayacamin Montip, Michael P. Kozar, Sean M. Curtis, Darshan S. Thota, Jing Zhang, Victor Melendez, Lucia Gerena |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Chalcone Spectrometry Mass Electrospray Ionization Plasmodium berghei Drug Resistance Pharmacology chemistry.chemical_compound Antimalarials Inhibitory Concentration 50 Mice Chalcones Pharmacokinetics Biotransformation In vivo Tandem Mass Spectrometry parasitic diseases Lethal infection Animals Humans Chromatography High Pressure Liquid Mice Inbred ICR biology Dose-Response Relationship Drug Molecular Structure General Medicine biology.organism_classification Survival Analysis In vitro Malaria chemistry Microsomes Liver Plasmodium yoelii Half-Life |
| Zdroj: | Pharmacology. 87(1-2) |
| ISSN: | 1423-0313 |
| Popis: | 4′-n-Butoxy-2,4-dimethoxy-chalcone (MBC) has been described as protecting mice from an otherwise lethal infection with Plasmodium yoelii when dosed orally at 50 mg/kg/dose, daily for 5 days. In contrast, we found that oral dosing of MBC at 640 mg/kg/dose, daily for 5 days, failed to extend the survivability of P. berghei-infected mice. The timing of compound administration and metabolic activation likely contribute to the outcome of efficacy testing in vivo. Microsomal digest of MBC yielded 4′-n-butoxy-4-hydroxy-2-methoxy-chalcone and 4′-(1-hydroxy-n-butoxy)-2,4-dimethoxy-chalcone. We propose that the latter will hydrolyze in vivo to 4′-hydroxy-2,4-dimethoxy-chalcone, which has greater efficacy than MBC in our P. berghei-infected mouse model and was detected in plasma following oral dosing of mice with MBC. Pharmacokinetic parameters suggest that poor absorption, distribution, metabolism and excretion properties contribute to the limited in vivoefficacy observed for MBC and its analogs. |
| Databáze: | OpenAIRE |
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