In vitro metabolism of the biguanide antimalarials in human liver microsomes: evidence for a role of the mephenytoin hydroxylase (P450 MP) enzyme.
The metabolic activation of the arylbiguanide antimalarials proguanil (PG) and chlorproguanil (CPG) has been investigated in liver microsomes from three human livers. All three microsomal preparations activated the biguanides. The kinetic parameters for PG metabolism to cycloguanil (CG) were Km 21.8, 29.6 and 26.4 microM and Vmax 1.5, 5.9, and 8.2 pmol min-1 mg-1. The values for CPG conversion to chlorcycloguanil (CCG) were Km 12.9, 19.7 and 26.1 microM and Vmax 5.7, 4.8 and 3.6 pmol min-1 mg-1. The metabolic activation of both biguanides was competitively inhibited by the anticonvulsant mephenytoin. Sparteine and tolbutamide had no effect on biguanide metabolism. These data suggest an involvement of the mephenytoin hydroxylase enzyme, which exhibits a genetic polymorphism in man, in the metabolic activation of the biguanide antimalarials.
Helsby
N A
NA
Department of Parasitology, Liverpool School of Tropical Medicine.
Ward
S A
SA
Howells
R E
RE
Breckenridge
A M
AM
D000962:Antimalarials / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases; D001711:Biotransformation; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008617:Mephenytoin / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D002727:Proguanil / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D013034:Sparteine / Q000494:pharmacology; D014044:Tolbutamide / Q000494:pharmacology
D000962:Antimalarials; D013034:Sparteine; C007030:chlorproguanil; D003577:Cytochrome P-450 Enzyme System; D014044:Tolbutamide; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D008617:Mephenytoin; D002727:Proguanil