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.