Role of specific cytochrome P450 isoforms in the conversion of phenoxypropoxybiguanide analogs in human liver microsomes to potent antimalarial dihydrotriazines
| Autor: | Jason C. Sousa, Kirsten S. Smith, Michael P. Kozar, Damaris S. Diaz, David P. Jacobus, Constance O. Asher, Donald R. Skillman, Todd W Shearer, Guy A. Schiehser, Wilbur K. Milhous |
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| Rok vydání: | 2007 |
| Předmět: |
Cycloguanil
CYP2D6 Proguanil Pharmaceutical Science CYP2C19 Pharmacology Antimalarials Cytochrome P-450 Enzyme System medicine Cytochrome P-450 Enzyme Inhibitors Humans Protein Isoforms Prodrugs Active metabolite CYP3A4 biology Triazines Cytochrome P450 Antibodies Monoclonal Prodrug Recombinant Proteins Biochemistry biology.protein Microsomes Liver medicine.drug |
| Zdroj: | Drug metabolism and disposition: the biological fate of chemicals. 36(2) |
| ISSN: | 1521-009X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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