The role of S-mephenytoin hydroxylase (CYP2C19) in the metabolism of the antimalarial biguanides.

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Wright JD, Helsby NA, Ward SA

The role of S-mephenytoin hydroxylase (CYP2C19) in the metabolism of the antimalarial biguanides.

Br J Clin Pharmacol. 1995 Apr;39(4):441-4.

PubMed ID

7640152 [ View in PubMed

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Abstract

The effects of the CYP2C19 substrates, mephenytoin, methsuximide and mephobarbitone on the metabolism of proguanil and chlorproguanil by human liver microsomes were studied. All of the CYP2C19 substrates significantly inhibited (P < 0.05) the formation of both cycloguanil and chlorcycloguanil from their parent compounds. In the presence of mephenytoin (50 and 100 microM) the extent of proguanil cyclisation was decreased by 66% and 67% whilst the cyclisation of chlorproguanil was decreased by 51% and 70%, respectively. Methsuximide (50 and 100 microM) inhibited cycloguanil formation by 68% and 77% and chlorcycloguanil formation by 43% and 58%, respectively. In the presence of mephobarbitone (50 and 100 microM) the cyclisation of proguanil and chlorproguanil to their active metabolites was reduced by 24% and 42% and 48% and 63%, respectively. In addition, proguanil and chlorproguanil were shown to be mutual competitive inhibitors of metabolism to their triazine metabolites. In the presence of proguanil (50 and 100 microM) the Km value for chlorcycloguanil production was increased by 118% and 200%, respectively, with little change in Vmax. Similarly, chorproguanil (50 microM) increased the Km for the in vitro cyclisation of proguanil by 50% with no alteration in Vmax. These data suggest that both chlorproguanil and proguanil are metabolised in vitro by mephenytoin hydroxylase, CYP2C19.

DrugBank Data that Cites this Article

Drugs

Methsuximide

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Methsuximide	Cytochrome P450 2C19	Protein	Humans	Unknown	Substrate Inhibitor	Details