(S)-Mephenytoin
(Synonyms: 甲秦皮素,(S)-5-Ethyl-3-methyl-5-phenylhydantoin) 目录号 : GC14486
S-Mephenytoin (5-phenyl-5-ethyl-N-methylhydantoin) 是一种抗惊厥药，通过 N-去甲基化和 4-羟基化（芳环）代谢。
Cas No.:70989-04-7
Sample solution is provided at 25 µL, 10mM.
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S-Mephenytoin (5-phenyl-5-ethyl-N-methylhydantoin) is an anticonvulsive drug which is metabolized by N-demethylation and 4-hydroxylation (of the aromatic ring). CYP2C19 genotype is a major determined factor for metabolisms of S-Mephenytoin. The formations of 4X-hydroxymephenytoin, S-Mephenytoin’s metabolite is CYP2C19 genotype dependent.[1][2]
The genetic polymorphism of CYP2C19 was revealed by the discovery of deficient 4’-hydroxylation of mephenytoin (3-methyl-5-phenyl-5 ethylhydantoin; Mesantoin). Human can be characterized as poor (PM) or extensive metabolizers (EM) with use of racemic mephenytoin as a phenotyping drug, and CYP2C19 has been identified as the major S-Mephenytoin (S-MP) hydroxylase in human. This polymorphism affects the metabolism of many other clinically important drugs such as diazepam, omeprazole (OP), imipramine, propranolol, and chloroguanide.[1]
Rabbit anti-human cytochrome b5 inhibited NADH-cytochrome-c reductase and S-Mephenytoin 4-hydroxylase activities in human liver microsomes. In the presence of cytochrome b5, the Km value for S-Mephenytoin was 1.25 mM with all five purified cytochrome P-450s preparations, and Vmax values were 0.8-1.25 nmol of 4-hydroxy product formed per min/nmol of P-450. P-45OMP is a relatively selective P-450 form that metabolizes substituted hydantoins well.[2]
References:
[1]. Zhou HH. CYP2C19 genotype determines enzyme activity and inducibility of S-Mephenytoin hydroxylase. Clin Chim Acta. 2001 Nov;313(1-2):203-8.
[2]. Shimada T, et al. Human liver microsomal cytochrome P-450 mephenytoin 4-hydroxylase, a prototype of genetic polymorphism in oxidative drug metabolism. Purification and characterization of two similar forms involved in the reaction. J Biol Chem. 1986 Jan 15;261(2):909-21.
S-Mephenytoin (5-phenyl-5-ethyl-N-methylhydantoin) 是一种抗惊厥药，通过 N-去甲基化和 4-羟基化（芳环）代谢。 CYP2C19 基因型是 S-美芬妥英代谢的主要决定因素。 S-Mephenytoin 的代谢物 4X-hydroxymephenytoin 的形成依赖于 CYP2C19 基因型。[1][2]
美苯妥英（3-甲基-5-苯基-5 乙基乙内酰脲；美山妥英）的 4'-羟基化缺陷的发现揭示了 CYP2C19 的遗传多态性。使用外消旋美苯妥英作为表型药物，人类可被表征为弱代谢者 (PM) 或强代谢者 (EM)，并且 CYP2C19 已被确定为人类中主要的 S-美芬妥英 (S-MP) 羟化酶。这种多态性影响许多其他临床重要药物的代谢，例如地西泮、奥美拉唑 (OP)、丙咪嗪、普萘洛尔和氯胍。[1]
兔抗人细胞色素 b5 抑制人肝微粒体中的 NADH-细胞色素-c 还原酶和 S-美芬妥英 4-羟化酶活性。在细胞色素 b5 存在的情况下，所有五种纯化的细胞色素 P-450 制剂的 S-美芬妥英的 Km 值为 1.25 mM，Vmax 值为每分钟/nmol P-450 形成的 4-羟基产物 0.8-1.25 nmol。 P-45OMP 是一种相对选择性的 P-450 形式，可以很好地代谢取代的乙内酰脲。[2]
| Cas No. | 70989-04-7 | SDF | |
| 别名 | 甲秦皮素,(S)-5-Ethyl-3-methyl-5-phenylhydantoin | ||
| 化学名 | (5S)-5-ethyl-3-methyl-5-phenyl-2,4-imidazolidinedione | ||
| Canonical SMILES | O=C1[C@@](C2=CC=CC=C2)(CC)NC(N1C)=O | ||
| 分子式 | C12H14N2O2 | 分子量 | 218.3 |
| 溶解度 | 15mg/ml in ethanol;25mg/ml in DMSO;25mg/ml in dimethyl formamide | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 4.5809 mL | 22.9043 mL | 45.8085 mL |
| 5 mM | 0.9162 mL | 4.5809 mL | 9.1617 mL |
| 10 mM | 0.4581 mL | 2.2904 mL | 4.5809 mL |
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Genetic polymorphism of S-mephenytoin hydroxylation
Genetic polymorphism of S-mephenytoin 4'-hydroxylation
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.
S-mephenytoin 4-hydroxylation in older Americans
To examine whether a drug-metabolizing enzyme changes with normal aging, the S:R index of S-mephenytoin 4-hydroxylation was determined in 150, unmedicated elderly Americans (mean age 75.4). Ten (6.7%) were identified as categorically slow metabolizers (S:R ratios greater than or equal to .95). This increased incidence of slow metabolizers was accounted for by a significant and previously unreported, increased proportion of slow metabolizers among the black (18.5%) as compared to the white subjects (4.1%) (P = .017). There was no relationship found between S:R ratios and age or creatinine clearance.
S-mephenytoin hydroxylation phenotypes in a Swedish population determined after coadministration with debrisoquin
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.
CYP2C19 genotype determines enzyme activity and inducibility of S-mephenytoin hydroxylase
Background: The association between decreased drug clearance and decreased activity of cytochrome P4502C19 (CYP2C19), the inherited nature of the deficiency, and its frequency and clinical importance were evaluated extensively in the past over one decade. There is an interethnic difference in the frequency of poor metabolizers and mutant alleles of CYP2C19 among Chinese nationalities. Different frequency of mutations that code for CYP2C19 results in interethnic differences in distribution of the polymorphic trait for this enzyme. CYP2C19 genotype is a major determined factor for metabolisms of S-mephenytoin (S-MP), diazepam, and omeprazole (OP). The formations of their metabolites, 4'-hydroxymephenytoin (4'-OH-MP), demethyldiazepam, and 5-hydroxyomeprazole (5-OH-OP) are CYP2C19 genotype dependent. The inducibility of CYP2C19 activity is also related to CYP2C19 genotype.
Conclusions: The availability of phenotyping and genotyping methods should help identify the adverse reaction and toxicity of drugs that metabolized by CYP2C19 and determine the doses of these drugs according to individual CYP2C19 genotype.