title: Role of specific cytochrome P450 isoforms in the conversion of phenoxypropoxybiguanide analogs in human liver microsomes to potent antimalarial dihydrotriazines.
abstract: 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.
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors.forename: Damaris S
authors.initials: DS
authors.lastname: Diaz
authors.forename: Michael P
authors.initials: MP
authors.lastname: Kozar
authors.forename: Kirsten S
authors.initials: KS
authors.lastname: Smith
authors.forename: Constance O
authors.initials: CO
authors.lastname: Asher
authors.forename: Jason C
authors.initials: JC
authors.lastname: Sousa
authors.forename: Guy A
authors.initials: GA
authors.lastname: Schiehser
authors.forename: David P
authors.initials: DP
authors.lastname: Jacobus
authors.forename: Wilbur K
authors.initials: WK
authors.lastname: Milhous
authors.forename: Donald R
authors.initials: DR
authors.lastname: Skillman
authors.forename: Todd W
authors.initials: TW
authors.lastname: Shearer
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000962:Antimalarials / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D011355:Prodrugs / Q000378:metabolism*; D002727:Proguanil / Q000031:analogs & derivatives* / Q000378:metabolism*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014227:Triazines / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000962:Antimalarials; D065607:Cytochrome P-450 Enzyme Inhibitors; D011355:Prodrugs; D020033:Protein Isoforms; D011994:Recombinant Proteins; D014227:Triazines; C082651:PS 15; C026009:cycloguanil; C006201:BRL 6231; D003577:Cytochrome P-450 Enzyme System; D002727:Proguanil