Nirvanol
(Synonyms: 5-乙基-5-苯基海因) 目录号 : GC49501
An active metabolite of mephenytoin
Cas No.:631-07-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Nirvanol is an active metabolite of mephenytoin, a substrate of the cytochrome P450 (CYP) isoform CYP2C19 with anticonvulsant activities.1 It blocks the hind leg tonic extensor phase in a mouse model of seizures induced by maximal electroshock (MES; ED50 = 30 mg/kg).
1.Kupferberg, H.J., and Yonekawa, W.The metabolism of 3-methyl-5-ethyl-5-phenylhydantoin (mephenytoin) to 5-ethyl-5-phenylhydantoin (nirvanol) in mice in relation to anticonvulsant activityDrug Metab. Dispos.3(1)26-29(1975)
| Cas No. | 631-07-2 | SDF | Download SDF |
| 别名 | 5-乙基-5-苯基海因 | ||
| Canonical SMILES | O=C(N1)C(C2=CC=CC=C2)(CC)NC1=O | ||
| 分子式 | C11H12N2O2 | 分子量 | 204.2 |
| 溶解度 | DMSO: soluble | 储存条件 | -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 4.8972 mL | 24.4858 mL | 48.9716 mL |
| 5 mM | 0.9794 mL | 4.8972 mL | 9.7943 mL |
| 10 mM | 0.4897 mL | 2.4486 mL | 4.8972 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
(+)-N-3-Benzyl-nirvanol and (-)-N-3-benzyl-phenobarbital: new potent and selective in vitro inhibitors of CYP2C19
Drug Metab Dispos 2002 Mar;30(3):235-9.PMID:11854139DOI:10.1124/dmd.30.3.235.
Highly potent and selective CYP2C19 inhibitors are not currently available. In the present study, N-3-benzyl derivatives of Nirvanol and phenobarbital were synthesized, their respective (+)- and (-)-enantiomers resolved chromatographically, and inhibitor potencies determined for these compounds toward CYP2C19 and other human liver cytochromes P450 (P450s). (-)-N-3-Benzyl-phenobarbital and (+)-N-3-benzyl-nirvanol were found to be highly potent, competitive inhibitors of recombinant CYP2C19, exhibiting K(i) values of 79 and 250 nM, respectively, whereas their antipodes were 20- to 60-fold less potent. In human liver preparations, (-)-N-3-benzyl-phenobarbital and (+)-N-3-benzyl-nirvanol inhibited (S)-mephenytoin 4'-hydroxylase activity, a marker for native microsomal CYP2C19, with K(i) values ranging from 71 to 94 nM and 210 to 280 nM, respectively. At single substrate concentrations of 0.3 microM [(-)-N-3-benzyl-phenobarbital] and 1 microM [(+)-N-3-benzyl-nirvanol] that were used to examine inhibition of a panel of cDNA-expressed P450 isoforms, neither CYP1A2, 2A6, 2C8, 2C9, 2D6, 2E1, nor 3A4 activities were decreased by greater than 16%. In contrast, CYP2C19 activity was inhibited approximately 80% under these conditions. Therefore, (+)-N-3-benzyl-nirvanol and (-)-N-3-benzyl-phenobarbital represent new, highly potent and selective inhibitors of CYP2C19 that are likely to prove generally useful for screening purposes during early phases of drug metabolism studies with new chemical entities.
The metabolism of 3-methyl-5-ethyl-5-phenylhydantoin (mephenytoin) to 5-ethyl-5-phenylhydantoin (Nirvanol) in mice in relation to anticonvulsant activity
Drug Metab Dispos 1975 Jan-Feb;3(1):26-9.PMID:234831doi
Mephenytoin (3-methyl-5-ethyl-5-phenylhydantoin) is metabolized to Nirvanol (5-ethyl-5-phenylhydantoin). Both compounds block the hind leg tonic extensor phase of the Maximal Electroshock Seizure (M.E.S.) Test in mice. The M.E.S. ED50 of mephenytoin is 42 mg/kh at 30 min and 35 mg/kg at 2 hr after ip administration. The M.E.S. ED50 for Nirvanol at 30 min and 2 hr was 23 and 30 mg/kg, respectively. Brain and plasma levels of mephenytoin and Nirvanol were determined by gas-liquid chromatography after ip administration of 40 mg of mephenytoin per kg. At 30 min the brain levels of mephenytoin and Nivanol were 19.2 and 8.1 mug/g, respectively. The brain levels of mephenytoin fell to 5.8 mug/g and those of Nirvanol rose to 18.2 mug/g at 2 hr. The total molar concentration of mephenytoin and Nirvanol, however, did not change more than 10% during the 2-hr period. Although the anticonvulsant activity of mephenytoin did not vary greatly during 2 hr after administration, the early activity is due in major part fo mephenytoin and the later activity to Nirvanol.
Relation of in vivo drug metabolism to stereoselective fetal hydantoin toxicology in mouse: evaluation of mephenytoin and its metabolite, Nirvanol
J Pharmacol Exp Ther 1982 Apr;221(1):228-34.PMID:7062285doi
Anticonvulsant therapy during pregnancy with the hydantoin phenytoin carries a risk of teratologic sequelae and developmental retardation known as the fetal hydantoin syndrome. The putative teratogen is a highly reactive arene oxide intermediate produced during phenytoin metabolism. By using two structurally similar hydantoins, mephenytoin and its in vivo demethylated metabolite Nirvanol, we examined the possibility for a stereoselective dissociation of fetal hydantoin toxicity from maternal anticonvulsant activity. The d-isomers (S-enantiomers) of mephenytoin and Nirvanol are p-hydroxylated via an arene oxide and hence were suspect teratogens. The l-isomers (R-enantiomers), being eliminated primarily via alternate pathways, were expected to be less toxic. Equimolar doses of the d- or l-isomers of mephenytoin or Nirvanol were administered to pregnant Swiss ICR mice i.p. on gestational day 10. An 8-fold increase in fetal resorptions and a significant 11% decrease in fetal body weight was observed in the group treated with l-nirvanol, whereas no or minimal toxicity was observed in the other treatment groups. The blood clearance for d-nirvanol was double that for l-nirvanol, with correspondingly higher urinary concentrations of arene oxide-mediated metabolites. ANIH shift during metabolism supported the presence of an arene oxide intermediate. Contrary to our expectations, only l-nirvanol, the isomer producing less arene oxide, demonstrated fetal toxicity, thus raising some doubt concerning the arene oxide as the putative hydantoin teratogen. Further animal studies with the d-isomers of mephenytoin and Nirvanol may lead to an anticonvulsant of choice during pregnancy.
Disposition of mephenytoin and its metabolite, Nirvanol, in epileptic patients
Neurology 1984 Aug;34(8):1100-2.PMID:6431315DOI:10.1212/wnl.34.8.1100.
We investigated the conversion of mephenytoin to Nirvanol in five patients with uncontrolled complex partial seizures. After a 50-mg single oral dose, mean peak mephenytoin level was 0.48 microgram/ml and Nirvanol 0.37 microgram/ml. After 400 mg, peak mephenytoin level was 3.9 micrograms/ml and Nirvanol 2.5 micrograms/ml. On 400 mg daily, mephenytoin reached a mean steady-state level of 1.5 micrograms/ml. Nirvanol mean steady-state level was 18 micrograms/ml. Mean plasma half-life was 17 hours for mephenytoin and 114 hours for Nirvanol. Two patients had reduced seizures during mephenytoin therapy and one a transient increase during drug withdrawal. No toxicity was seen, but mephenytoin was not more effective than phenytoin.
Enantiospecific separation and quantitation of mephenytoin and its metabolites Nirvanol and 4'-hydroxymephenytoin in human plasma and urine by liquid chromatography/tandem mass spectrometry
Rapid Commun Mass Spectrom 2006;20(3):463-72.PMID:16395737DOI:10.1002/rcm.2324.
A sensitive method using enantiospecific liquid chromatography/tandem mass spectrometry detection for the quantitation of S- and R-mephenytoin as well as its metabolites S- and R-nirvanol and S- and R-4'-hydroxymephenytoin in plasma and urine has been developed and validated. Plasma samples were prepared by protein precipitation with acetonitrile, while urine samples were diluted twice with the mobile phase before injection. The analytes were then separated on a chiral alpha(1)-acid glycoprotein (AGP) column and thereafter detected, using electrospray ionization tandem mass spectrometry. In plasma, the lower limit of quantification (LLOQ) was 1 ng/mL for S- and R-4'-hydroxymephenytoin and S-nirvanol and 3 ng/mL for R-nirvanol and S- and R-mephenytoin. In urine, the LLOQ was 3 ng/mL for all compounds. Resulting plasma and urine intra-day precision values (CV) were <12.4% and <6.4%, respectively, while plasma and urine accuracy values were 87.2-108.3% and 98.9-104.8% of the nominal values, respectively. The method was validated for plasma in the concentration ranges 1-500 ng/mL for S- and R-4'-hydroxymephenytoin, 1-1000 ng/mL for S-nirvanol, and 3-1500 ng/mL for R-nirvanol and S- and R-mephenytoin. The validated concentration range in urine was 3-5000 ng/mL for all compounds. By using this method, the metabolic activities of two human drug-metabolizing enzymes, cytochrome P450 (CYP) 2C19 and CYP2B6, were simultaneously characterized.