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1.
Pharmacology ; 87(1-2): 96-104, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21282967

RESUMO

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 vivo efficacy observed for MBC and its analogs.


Assuntos
Antimaláricos/farmacocinética , Chalconas/farmacocinética , Malária/tratamento farmacológico , Microssomos Hepáticos/metabolismo , Plasmodium berghei/efeitos dos fármacos , Animais , Antimaláricos/sangue , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Biotransformação , Chalconas/sangue , Chalconas/farmacologia , Chalconas/uso terapêutico , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Resistência a Medicamentos , Meia-Vida , Humanos , Concentração Inibidora 50 , Malária/sangue , Malária/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Espectrometria de Massas por Ionização por Electrospray , Análise de Sobrevida , Espectrometria de Massas em Tandem
2.
Drug Metab Dispos ; 36(2): 380-5, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18006651

RESUMO

Phenoxypropoxybiguanides, such as PS-15, are antimalarial prodrugs analogous to the relationship of proguanil and its active metabolite cycloguanil. Unlike cycloguanil, however, WR99210, the active metabolite of PS-15, has retained in vitro potency against newly emerging antifolate-resistant malaria parasites. Recently, in vitro metabolism of a new series of phenoxypropoxybiguanide analogs has examined the production of the active triazine metabolites by human liver microsomes. The purpose of this investigation was to elucidate the primary cytochrome P450 isoforms involved in the production of active metabolites in the current lead candidate. By using expressed human recombinant isoform preparations, specific chemical inhibitors, and isoform-specific inhibitory antibodies, the primary cytochrome P450 isoforms involved in the in vitro metabolic activation of JPC-2056 were elucidated. Unlike proguanil, which is metabolized primarily by CYP2C19, the results indicate that CYP3A4 plays a more important role in the metabolism of both PS-15 and JPC-2056. Whereas CYP2D6 appears to play a major role in the metabolism of PS-15 to WR99210, it appears less important in the conversion of JPC-2056 to JPC-2067. These results are encouraging, considering the prominence of CYP2C19 and CYP2D6 polymorphisms in certain populations at risk for contracting malaria, because the current clinical prodrug candidate from this series may be less dependent on these enzymes for metabolic activation.


Assuntos
Antimaláricos/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Pró-Fármacos/metabolismo , Proguanil/análogos & derivados , Proguanil/metabolismo , Anticorpos Monoclonais/farmacologia , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/genética , Humanos , Microssomos Hepáticos/metabolismo , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Recombinantes/metabolismo , Triazinas/metabolismo
3.
Bioorg Med Chem Lett ; 16(21): 5682-6, 2006 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-16908136

RESUMO

Investigation of a series of 1-phenyl-3-aryl-2-propen-1-ones resulted in the identification of nine inhibitors with submicromolar efficacy against at least one Plasmodium falciparum strain in vitro. These inhibitors were inactive when given orally in a Plasmodium berghei infected mouse model. Significant compound degradation occurred upon their exposure to a liver microsome preparation, suggesting metabolic instability may be responsible for the lack of activity in vivo.


Assuntos
Antimaláricos/farmacologia , Antimaláricos/farmacocinética , Cetonas/farmacologia , Cetonas/farmacocinética , Plasmodium falciparum/efeitos dos fármacos , Animais , Malária Falciparum/tratamento farmacológico , Camundongos , Microssomos Hepáticos/fisiologia
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