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The role of S‐mephenytoin hydroxylase (CYP2C19) in the metabolism of the antimalarial biguanides.
Author(s) -
Wright JD,
Helsby NA,
Ward SA
Publication year - 1995
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.1995.tb04474.x
Subject(s) - mephenytoin , cyp2c19 , pharmacology , medicine , chemistry , metabolism , cytochrome p450
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.