Stereoselective 4'-hydroxylation of phenytoin: relationship to (S)-mephenytoin polymorphism in Japanese.
OBJECTIVE
The aim of this study was to clarify whether phenytoin (PHT) stereoselective hydroxylation cosegregates with (S)-mephenytoin phenotype.


METHODS
A single dose of PHT (100 mg) was administered orally to six healthy Japanese subjects in whom the genotype and phenotype of CYP2C19 had been determined previously. The urinary excretion profiles of the metabolites of PHT, (R)- and (S)-p-HPPH [5-(4-hydroxyphenyl)-5-phenylhydantoin] up to 361 postdose were compared between the two groups of poor metabolizers (PMs, n = 3) and extensive metabolizers (EMs, n = 3) with respect to CYP2C19. CYP2C9 genotype was also determined.


RESULTS
All the alleles were found to be wild type (Arg144 Tyr358Ile359Gly417) in each subject. The mean value for cumulative urinary excretion of unchanged PHT was not significantly different between the PMs and the EMs. However, recovery of (R)-p-HPPH at 36 h was 3.5-fold lower and that of (S)-p-HPPH 1.3-fold lower in PMs than in EMs. Although the mean urinary excretion values for both metabolites were significantly lower in the PMs than in the EMs, the difference between the two groups was larger for (R)-p-HPPH. A significant negative correlation was observed between the hydroxylation index of omeprazole (the ratio between the serum concentrations of omeprazole and hydroxyomeprazole in blood samples drawn 3 h after drug intake) and the log10 0-12 h urinary recovery of (R)-p-HPPH.


CONCLUSIONS
In humans, the 4'-hydroxylation of PHT is highly stereoselective towards formation of the (S)-enantiomer. Thus, (S)-hydroxylation by CYP2C9 might be the major determinant of the disposition of PHT. However, these results support the hypothesis that the stereoselective hydroxylation pathway of PHT to form (R)-p-HPPH cosegregates with the CYP2C19 metabolic polymorphism.
Ieiri
I
I
Division of Pharmaceutical Sciences, Kyushu University, Japan.
Mamiya
K
K
Urae
A
A
Wada
Y
Y
Kimura
M
M
Irie
S
S
Amamoto
T
T
Kubota
T
T
Yoshioka
S
S
Nakamura
K
K
Nakano
S
S
Tashiro
N
N
Higuchi
S
S
D000284:Administration, Oral; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases; D002851:Chromatography, High Pressure Liquid; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D005838:Genotype; D006720:Homozygote; D006801:Humans; D006900:Hydroxylation; D007564:Japan; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009853:Omeprazole / Q000652:urine; D010641:Phenotype; D010672:Phenytoin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry / Q000652:urine*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D013237:Stereoisomerism; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics*
C001419:hydroxyphenytoin; D010672:Phenytoin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D039181:Steroid 16-alpha-Hydroxylase; D009853:Omeprazole