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Epilepsia Dec 1976Serum levels of mephenytoin (Mesantoin) and its metabolite nirvanol were correlated with effectiveness and side effects in 93 patients. Mean mephenytoin level was 8% of...
Serum levels of mephenytoin (Mesantoin) and its metabolite nirvanol were correlated with effectiveness and side effects in 93 patients. Mean mephenytoin level was 8% of the combined mephenytoin plus nirvanol levels. "Total mephenytoin" level should be used clinically, as neither individual component is as well correlated with clinical phenomena. Serum levels of 25 to 40 mug/ml usually yield improvement in seizure control without discomfort, and three-quarters of patients had fewer seizures. Side effects frequently associated with phenytoin were absent, but drowsiness, an occasional rash, and a single, fatal case of aplastic anemia were found. Performance on psychological tests of cognitive-attentional skills showed a modest improvement during mephenytoin administration. The drug merits wider employment in refractory seizure problems, but vigilant follow-up is required.
Topics: Adolescent; Adult; Anemia, Aplastic; Anticonvulsants; Chemical Phenomena; Chemistry; Drug Evaluation; Epilepsy; Follow-Up Studies; Humans; Hydantoins; Mephenytoin
PubMed: 1001284
DOI: 10.1111/j.1528-1157.1976.tb04452.x -
Pharmacology & Therapeutics 1989
Review
Topics: Animals; Humans; Hydantoins; Hydroxylation; Mephenytoin; Molecular Biology; Polymorphism, Genetic
PubMed: 2675129
DOI: 10.1016/0163-7258(89)90047-8 -
Xenobiotica; the Fate of Foreign... 19921. Stereoselective 4'-hydroxylations of R-(--)-mephenytoin and S-(+)-mephenytoin were determined in liver microsomes of 19 Japanese subjects. 2. The content of P-450... (Review)
Review
1. Stereoselective 4'-hydroxylations of R-(--)-mephenytoin and S-(+)-mephenytoin were determined in liver microsomes of 19 Japanese subjects. 2. The content of P-450 human-2 assessed by Western-blots correlated with microsomal S-(+)-mephenytoin 4'-hydroxylation. Antibody raised against P-450 human-2 effectively inhibited microsomal S-(+)-mephenytoin 4'-hydroxylation, but was less efficient for inhibition of R-(--)-mephenytoin 4'-hydroxylation in extensive metabolizers, and 4'-hydroxylation of both mephenytoin enantiomers in poor metabolizers. 3. Similar results were observed on the stereoselective hydroxylations of R-(--)- and S-(+)-hexobarbital. Clear correlations were observed for the content of P-450 human-2 and microsomal R-(--)-hexobarbital 3'alpha-hydroxylation and S-(+)-hexobarbital 3'beta-hydroxylation. 4. Moreover, yeast microsomes expressing P-450 human-2 cDNA showed high stereoselectivities for hydroxylations of mephenytoin and hexobarbital similar to those observed in human liver. 5. Two other cytochromes P-450(IIC 9/10) expressed in yeast, whose cDNA were synthesized by site-directed mutagenesis from human-2 cDNA, showed no stereoselectivity for the hydroxylations of mephenytoin and hexobarbital, in spite of the modification of only two amino acid substitutions or deletions in the whole sequence. 6. Only a cytochrome derived from P-450 human cDNA corresponding to P-450 human-2 was expressed in human livers, the two cytochromes of the three related IIC9/10 forms were not expressed. 7. These findings indicate that P-450 human-2 is the major cytochrome P-450 responsible for the polymorphisms in stereoselective hydroxylations of mephenytoin and hexobarbital.
Topics: Cytochrome P-450 Enzyme System; DNA; Hexobarbital; Humans; Hydroxylation; Liver; Mephenytoin; Mixed Function Oxygenases; Polymorphism, Genetic; Stereoisomerism
PubMed: 1441599
DOI: 10.3109/00498259209051862 -
Progress in Clinical and Biological... 1986
Comparative Study Review
Topics: Animals; Aryl Hydrocarbon Hydroxylases; Chemical Phenomena; Chemistry; China; Cytochrome P-450 CYP2C19; Debrisoquin; Dogs; Ethnicity; Humans; Hydantoins; Hydroxylation; Japan; Kinetics; Liver; Mephenytoin; Mephobarbital; Mice; Mixed Function Oxygenases; Ontario; Phenotype; Polymorphism, Genetic; Sparteine; Tennessee; White People
PubMed: 3523505
DOI: No ID Found -
Psychopharmacology Bulletin 1996The anticonvulsant drug mephenytoin is available as a racemic mixture of the S and R enantiomers. The S enantiomer is selectively 4'-hydroxylated in the liver by the... (Review)
Review
The anticonvulsant drug mephenytoin is available as a racemic mixture of the S and R enantiomers. The S enantiomer is selectively 4'-hydroxylated in the liver by the cytochrome P450 enzyme, CYP2C19. This reaction has a polymorphic distribution in human populations. Racemic mephenytoin has been extensively used as a probe drug to assign metabolic phenotypes for this genetically-determined polymorphism. Specific base substitution mutations in the CYP2C19 gene are responsible for the poor metabolism (PM) phenotype which is inherited as a recessive autosomal trait. The poor metabolizers (PMs) of S-mephenytoin are homozygous for these mutations. In contrast, extensive metabolizers (EMs) are either heterozygous or homozygous for the wild-type allele(s). Poor metabolizers have the inactive enzyme and therefore have reduced ability to metabolize substrates of CYP2C19, many of which are psychotropic drugs. Genotyping an individual before treatment with substrates of CYP2C19 will reduce the risk of side effects and improve compliance in PMs. The prevalence of PMs is relatively low in African-Americans and Caucasians and is as high as 20 percent in Asian populations.
Topics: Ethnicity; Humans; Hydroxylation; Mephenytoin; Polymorphism, Genetic; Prevalence
PubMed: 8783891
DOI: No ID Found -
Clinical Pharmacology and Therapeutics May 1989Mephenytoin (100 mg) and debrisoquin (10 mg) were administered orally, both separately and together, to 41 healthy subjects. The ratios between the S and R enantiomers...
Mephenytoin (100 mg) and debrisoquin (10 mg) were administered orally, both separately and together, to 41 healthy subjects. The ratios between the S and R enantiomers of mephenytoin and between debrisoquin and 4-OH-debrisoquin in urine were determined by use of GC. These ratios were used as measures of drug hydroxylation. There was no change in the phenotypic trait values of the two drugs when they were coadministered. Mephenytoin and debrisoquin then were coadministered to 253 healthy Swedish subjects, before bedtime, and urine samples were collected at periods of 0 to 8, 8 to 24, and 24 to 32 hours after drug administration. In the first sample, seven of the 253 subjects (2.8%, 95% confidence interval 0.8% to 4.8%) had an S/R ratio of greater than 0.8; this indicated that they were poor hydroxylators of S-mephenytoin. In the two consecutive samples, the S/R ratios of mephenytoin did not change in these seven persons, whereas it decreased to less than 0.2 in the third sample in the extensive hydroxylators. As was reported before, there was no relationship between the mephenytoin S/R ratio and the debrisoquin metabolic ratio (rs = 0.01). Coadministration of debrisoquin and mephenytoin before bedtime and urine collection during two consecutive nights allow for an accurate determination of both phenotypes in the population.
Topics: Adolescent; Adult; Aged; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C19; Cytochrome P-450 Enzyme System; Debrisoquin; Drug Interactions; Female; Humans; Hydantoins; Hydroxylation; Isoquinolines; Male; Mephenytoin; Middle Aged; Mixed Function Oxygenases; Phenotype; Sweden
PubMed: 2721104
DOI: 10.1038/clpt.1989.63 -
Clinical Pharmacology and Therapeutics Dec 1984The ability of normal subjects to hydroxylate mephenytoin (100 mg) or debrisoquine (10 mg) after oral dosing was investigated in 156 unrelated Caucasians living in...
The ability of normal subjects to hydroxylate mephenytoin (100 mg) or debrisoquine (10 mg) after oral dosing was investigated in 156 unrelated Caucasians living in middle Tennessee. Urinary recovery of 4-hydroxymephenytoin (4-OH-M) and the urinary S:R enantiomeric ratio of mephenytoin measured in an 8-hr urine sample were investigated as phenotypic traits for mephenytoin, and the urinary metabolic ratio of debrisoquine was used to determine the debrisoquine hydroxylase phenotype. Both urinary 4-OH-M and the S:R ratio of mephenytoin discriminated between extensive (EM) and poor (PM) metabolizers of mephenytoin. The frequencies of PMs for mephenytoin and debrisoquine hydroxylation activity were 2.6% and 7.0%. These two defects in oxidative metabolism were not observed in the same subjects, which suggests that 4-hydroxylation of mephenytoin is a new polymorphism independent of that for debrisoquine.
Topics: Administration, Oral; Adolescent; Adult; Chromatography, High Pressure Liquid; Debrisoquin; Female; Humans; Hydantoins; Hydroxylation; Male; Mephenytoin; Middle Aged; Phenotype; Polymorphism, Genetic; Tennessee; White People
PubMed: 6499356
DOI: 10.1038/clpt.1984.256 -
Clinical Pharmacology and Therapeutics Nov 1984The frequency of genetically deficient hydroxylation of mephenytoin (M-defect) was studied in 83 healthy Caucasians living in Toronto. The M-defect was compared with the...
The frequency of genetically deficient hydroxylation of mephenytoin (M-defect) was studied in 83 healthy Caucasians living in Toronto. The M-defect was compared with the widely studied genetic polymorphism of sparteine/debrisoquine oxidations (S-defect). After ingestion of mephenytoin and sparteine, urine samples (0 to 24 hr) were analyzed for p(4')-hydroxymephenytoin and urine samples over 0 to 12 hr were analyzed for sparteine and 2-and 5-dehydrosparteine by gas chromatographic methods. Nirvanol, the N-demethylation product of mephenytoin, was determined by a newly developed gas chromatographic/mass spectrometric method. Frequency distributions of both p-hydroxymephenytoin and dehydrosparteine excreted in urine were discontinuous (bimodal), while nirvanol and sparteine data were normally distributed. Two poor metabolizers of mephenytoin excreted 2% to 3% of the dose as p-hydroxymephenytoin and excreted normal amounts of nirvanol, but they were extensive metabolizers of sparteine. Six poor metabolizers of sparteine were found to be extensive metabolizers of mephenytoin (34% to 42% excreted in urine as p-hydroxyme-phenytoin). Thus the M-defect occurs among Canadian Caucasians with a frequency of 2% (0.0% to 7.5% with a confidence limit of 99%) and is independent of the S-defect.
Topics: Administration, Oral; Adult; Aged; Female; Gas Chromatography-Mass Spectrometry; Humans; Hydantoins; Hydroxylation; Male; Mephenytoin; Middle Aged; Pharmacogenetics; Sparteine; White People
PubMed: 6488688
DOI: 10.1038/clpt.1984.238 -
British Journal of Clinical Pharmacology May 2001To further evaluate mephenytoin as a probe for CYP2C19 phenotyping.
AIMS
To further evaluate mephenytoin as a probe for CYP2C19 phenotyping.
METHODS
Healthy subjects (n = 2638) were phenotyped using the urinary (S)-mephenytoin to (R)-mephenytoin ratio. This method was evaluated for (a) the stability of the S/R-ratio following sample storage, (b) the intraindividual reproducibility of the ratio, and (c) the occurrence of adverse events.
RESULTS
After prolonged storage, the S/R-ratio of samples from extensive metabolisers (EM) increased up to 85%. In 1.5% of the cases (1 out 66), this led to incorrect classification of phenotype. In EMs, but not in poor metabolisers (PMs), the S/R-ratio increased after acid treatment. The intraindividual reproducibility of the mephenytoin phenotyping procedure was 28%. No major side-effects were observed and there was no relationship between the incidence of side-effects and the phenotype of the subject.
CONCLUSIONS
After prolonged storage the S/R-ratio significantly increased in EMs and, although low, the risk of incorrect classification should not be ignored. Our data support the use of mephenytoin as a safe drug for CYP2C19 phenotyping.
Topics: Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C19; Cytochrome P-450 Enzyme System; Drug Stability; Drug Storage; Female; Humans; Male; Mephenytoin; Mixed Function Oxygenases; Phenotype; Reproducibility of Results; Substrate Specificity
PubMed: 11422005
DOI: 10.1046/j.1365-2125.2001.01331.x -
British Journal of Clinical Pharmacology May 1989The oxidation of mephenytoin was polymorphic in 358 healthy Danish volunteers. The ratio between the chromatographic peak areas of (S)- and (R)-mephenytoin (S/R) in 12 h...
The oxidation of mephenytoin was polymorphic in 358 healthy Danish volunteers. The ratio between the chromatographic peak areas of (S)- and (R)-mephenytoin (S/R) in 12 h urine was less than or equal to 0.48 in 349 extensive metabolizers (EM) and greater than or equal to 1 in 9 (2.5%) poor metabolizers (PM). Concomitant intake of mephenytoin and sparteine and subsequent assay by gas chromatography had no influence on the test results (mephenytoin S/R ratio or sparteine metabolic ratio). Among ten parents and seven siblings to six unrelated PM of mephenytoin only one (1/17 = 5.9%) was a PM. The pedigrees were compatible with an autosomal recessive mode of inheritance.
Topics: Adolescent; Adult; Chromatography, Gas; Denmark; Female; Humans; Hydantoins; Male; Mephenytoin; Middle Aged; Oxidation-Reduction; Phenotype; Polymorphism, Genetic; Sparteine
PubMed: 2757884
DOI: 10.1111/j.1365-2125.1989.tb03426.x