Caution in the use of a 100 mg dose of racemic mephenytoin for phenotyping southeastern Oriental subjects [letter]

Setiabudy, Rianto; Chiba, Kazuhiro; Kusaka, Meizoh; Ishizaki, Takashi

doi:10.1111/j.1365-2125.1992.tb04099.x

Cited by 18 publications

(11 citation statements)

References 6 publications

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“…The reason for this discrepancy is not clear. Our study does not support the view that subjects from Southeast Asia are more prone to adverse effects after intake of 100 mg mephenytoin than whites [23]. No PMs were found in the Vietnamese and this is in agreement with the frequency of about 1% reported in Japanese and Chinese [9,12].…”

Section: Discussioncontrasting

confidence: 77%

Proguanil metabolism is determined by the mephenytoin oxidation polymorphism in Vietnamese living in Denmark.

Brøsen¹,

Skjelbo²,

Flachs³

1993

Brit J Clinical Pharma

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1 A sparteine/mephenytoin phenotyping test was carried out in 37 Vietnamese living in Denmark. By visual inspection the urinary S/R-mephenytoin ratio appeared to show a bimodal frequency distribution. Eight putative poor metabolizers of mephenytoin, PMm (22%), had S/R-mephenytoin ratios from 0.79 to 1.12 and 29 putative extensive metabolizers of mephenytoin, EMm, had S/R-mephenytoin ratios S 0.55. All of the subjects were extensive metabolizers of sparteine with urinary metabolic ratios from 0.15 to 2.4. 2 The metabolism of the antimalarial prodrug proguanil was studied in 34 of the subjects after a single oral dose of 100 mg. The median 12 h urinary recoveries of the active metabolite cycloguanil and the minor metabolite 4-chlorphenylbiguanide were 5.8 and 1.9% of the dose, respectively, in 26 EMm compared with 1.6 and 0.4%, respectively, in 8 PMm (P < 0.001, Mann-Whitney U-test).3 There was no statistically significant correlation (Spearmans r,) between any index of proguanil metabolism and the sparteine metabolic ratio.

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Section: Discussioncontrasting

confidence: 77%

Proguanil metabolism is determined by the mephenytoin oxidation polymorphism in Vietnamese living in Denmark.

Brøsen¹,

Skjelbo²,

Flachs³

1993

Brit J Clinical Pharma

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“…The inference is that the CYP2C19 PM phenotype affects response to and dose of diazepam, but no controlled studies in PM and EM subjects have been reported to confirm this. Mephenytoin does produce greater sedation in Oriental subjects and those without the CYP2C19 enzyme [2,82], and it is assumed this also accounts for the difference in mephobarbital side effects in Japanese (20%) compared with Caucasians in Australia (3.5%) [54]. Lansoprazole, omeprazole and pantoprazole inhibit gastric acid secretion by the same mechanism, are structurally similar and thus are expected to have a similar constellation of side effects in PM subjects.…”

Section: Effects Of Cyp2c19 Polymorphism On Drug Metabolism and Responsementioning

confidence: 99%

The CYP2C19 Enzyme Polymorphism

2000

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The genetic test is gradually replacing probe drugs as the primary tool for screening populations for the CYP2C19 polymorphism. A full appreciation for the clinical and toxicological relevance of this genetic variation is presently limited. Further research is needed in several areas. The development and use of 3-D models of the CYP2C19 enzyme to automate and increase the rate at which CYP2C19 substrates are identified could reap great benefits. Meanwhile, clinical research should begin to determine whether the CYP2C19 polymorphism affects therapeutic outcomes and toxicity of drugs in actual patient settings. Combining research efforts in molecular modeling, genetic testing, clinical and epidemiological research will be required if better appreciation of this genetic variation and its importance in the population at large is to emerge.

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“…The phenotyping method was the same as reported previously by our group [18,19], except that the test dose of rac-mephenytoin was reduced from the conventional 100 to 50 mg because of marked sedative effects encountered in some of our subjects [20]. Individuals with a logl0 percentage urinary excretion of 4'-hydroxymephenytoin (calculated on a molar basis relative to an oral 50 mg dose of rac-mephenytoin) < 0.6 were classified as PM of S-mephenytoin [22].…”

Section: Subjectsmentioning

confidence: 99%

Metabolic disposition of proguanil in extensive and poor metabolisers of S‐mephenytoin 4'‐hydroxylation recruited from an Indonesian population.

Setiabudy

Kusaka

Chiba

et al. 1995

Brit J Clinical Pharma

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1 The metabolism of proguanil (PG) was studied by measuring PG, cycloguanil (CG) and 4-chlorophenylbiguanide (CPB) in plasma and urine samples after an oral 200 mg dose of PG hydrochloride administered to 14 extensive (EMs) and 10 poor hydroxylators (PMs) of S-mephenytoin of Indonesian origin.2 The mean (± s.d.) values of the elimination half-life (ti/2) and AUC of PG were significantly (P < 0.01) greater in the PM than in the EM group (20.6 ± 3.1 vs 14.6 ± 3.5 (95% confidence intervals of difference 3.1 to 8.9) h; and 5.43 ± 1.89 vs 3.68 ± 0.83 (0.58 to 2.91) gg ml-1 h).3 Plasma concentrations of CG, an active metabolite, could not be detected in all PMs, and those of CPB were sufficiently high to determine a time-course in only four PMs. Mean AUC(0,24 h) values of CPB were significantly (P < 0.05) lower in the PM (n = 4) than in the EM group (n = 14) (0.47 ± 0.13 vs 0.88 ± 0.50 (-0.14 to 0.96) ,ug ml-1 h). (rs = -0.831) metabolic ratios.6 The bioactivation of PG to CG cosegregates with the genetically determined 4'-hydroxylation polymorphism of S-mephenytoin in Indonesian subjects, and the formation of CPB appears to be associated partially with S-mephenytoin 4'-hydroxylation.

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Caution in the use of a 100 mg dose of racemic mephenytoin for phenotyping southeastern Oriental subjects [letter]

Cited by 18 publications

References 6 publications

Proguanil metabolism is determined by the mephenytoin oxidation polymorphism in Vietnamese living in Denmark.

Proguanil metabolism is determined by the mephenytoin oxidation polymorphism in Vietnamese living in Denmark.

The CYP2C19 Enzyme Polymorphism

Metabolic disposition of proguanil in extensive and poor metabolisers of S‐mephenytoin 4'‐hydroxylation recruited from an Indonesian population.

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