Meprobamate is rapidly metabolized in the liver. Meprobamate can induce liver microsomal enzymes and thus may at least theoretically alter the metabolism of other drugs such as warfarin. There is some evidence that meprobamate may accelerate its own metabolism. Meprobamate metabolites are inactive and include 2B-hydroxymeprobamate, and glucosyluronide and glucuronide conjugates of meprobamate. These metabolites are excreted by the kidneys. About 10-12% of a dose of meprobamate is excreted in urine as unchanged drug within 24 hr. The remainder is excreted in urine as metabolites.
来源:Hazardous Substances Data Bank (HSDB)
代谢
大部分药物在肝脏中代谢，主要转化为一侧链羟基衍生物和葡萄糖醛酸苷；消除动力学可能取决于剂量。
Most of the drug is metabolized in the liver, mainly to a side-chain hydroxy derivative and a glucuronide; the kinetics of elimination may depend on the dose.
A whole-body exposure of rats to 8 Gy radiation is ineffective in 3 days, and in 6 days, it prolongs considerably the effect and increases the pharmacological activity of hexenal, meprobamate, ethylmorphine, and amidopyrine, inhibits the activity of amidopyrine demethylase, aniline hydroxylase, NADPH-cytochrome c reductase, and reduces the content of protein, cytochromes P-450 and b5 in a microsomal liver fraction.
Carisoprodol is metabolized to meprobamate by the cytochrome P450 enzyme CYP2C19, encoded by the polymorphic CYP2C19 gene. Most studies on carisoprodol metabolism have been carried out on individuals phenotyped for CYP2C19 activity using the probe drug S-mephenytoin. /The investigators/ aimed to investigate whether the ratio of carisoprodol to meprobamate in a 'real life' setting could be predicted by CYP2C19 genotype or, more specifically, if high carisoprodol : meprobamate ratios in drugged drivers could be ascribed to the presence of mutant CYP2C19 alleles. From original material comprising 358 blood samples from apprehended drivers, two polarized groups were selected; a high-ratio group of 11 subjects where the carisoprodol : meprobamate ratio was >1 and a low-ratio control group of 23 subjects where the ratio was <0.31. Genotyping was carried out for the CYP2C19*2, CYP2C19*3 and CYP2C19*4 alleles. DNA samples from 94 healthy blood donors were used as reference material. The number of mutant alleles in the high-ratio and low-ratio groups was significantly higher and lower, respectively, than in the reference material. The increased number of mutant alleles in the high-ratio group was not due to the presence of many poor metabolizers, but to a high number of heterozygous individuals with the genotype CYP2C19*1/*2. This result indicates a gene dosage effect where the carisoprodol : meprobamate ratio reflects the number of active CYP2C19 alleles. The metabolism of carisoprodol to meprobamate is dependent on CYP2C19 genotype. Heterozygous individuals with the CYP2C19*1/*2 genotype have a reduced capacity for metabolizing carisoprodol, and should probably be regarded as intermediate metabolizers of this drug. /Carisoprodol/
Rates of serum enzyme elevations during meprobamate therapy have not been reported. While instances of clinically apparent liver injury due to meprobamate have been mentioned in review articles, no cases with specific information on clinical features have appeared in the published literature. Thus, meprobamate may be capable of causing clinically apparent liver injury, but it must be rare. Meprobamate is metabolized in the liver via the cytochrome P450 system and has major potential for drug-drug interactions. Meprobamate can exacerbate symptoms of porphyria. Serious allergic reactions to meprobamate have been reported including Stevens Johnson syndrome. In cases of meprobamate overdose, the cause of death has been respiratory suppression and not liver failure, although liver histology was not well defined.
Likelihood score: E* (unproven but suspected cause of liver injury).
Drug Class: Sedatives and Hypnotics, Miscellaneous
参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: 按照在人体内发展药物诱导肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
The concentrations of meprobamate in the blood and liver were determined in 12 cases of death due to meprobamate poisoning and in 29 cases of death due to the combined effects of meprobamate and alcohol, meprobamate and barbiturate, or meprobamate, alcohol and barbiturate. In the cases of poisoning from meprobamate alone, the blood meprobamate concentrations were within the range of 142-342 ug/mL. (mean value, 226 ug./mL). In the cases of poisoning with a combination of the drugs, the blood meprobamate concentrations were: for meprobamate and alcohol, 43-155 ug/mL (mean value, 117 ug/mL); for meprobamate and barbiturate, 30-276 ug/mL (mean value, 117 ug/mL); for meprobamate, barbiturate and alcohol, 33-460 ug/mL (mean value, 133 ug/mL).
Profound meprobamate intoxication is associated with plasma levels of 20 mg/100mL. Most pt appear to be comatose at levels about 10 mg/100 mL, whereas consciousness occurs at levels below 5 mg/100 mL.
The effect of hemoperfusion based on pharmacokinetic parameters in 4 cases of severe meprobamate intoxication is described. Maximal plasma levels reached 800, 816, 963 and 923 umol/L. All patients survived without sequelae including one patient resuscitated from cardiac arrest. The amount of meprobamate removed by hemoperfusion ranged from 1.6-6.2 g. Results suggest that hemoperfusion may be indicated in severe meprobamate intoxication.
Meprobamate is well absorbed from the GI tract following oral administration. Plasma concentrations of meprobamate required for sedative or hypnotic effects are not known. Oral administration of 400 mg of meprobamate produces peak plasma concentrations of 5-39 ug/mL within 1-3 hr. Plasma concentrations of 30-100 ug/mL are usually reached following mild overdosage and are associated with stupor or light coma. Plasma concentrations of 100-200 ug/mL are associated with deep coma and are potentially lethal; fatalities frequently occur when plasma concentrations exceed 200 ug/mL. The onset of sedative action is usually less than 1 hour following oral administration of meprobamate.
The present invention relates compounds of the formula: or pharmaceutically acceptable salts thereof, useful as sodium channel blockers, as well as compositions containing the same, processes for the preparation of the same, and therapeutic methods of use therefore in promoting hydration of mucosal surfaces and the treatment of diseases including cystic fibrosis, chronic obstructive pulmonary disease, asthma, bronchiectasis, acute and chronic bronchitis, emphysema, and pneumonia.
CHLORO-PYRAZINE CARBOXAMIDE DERIVATIVES WITH EPITHELIAL SODIUM CHANNEL BLOCKING ACTIVITY
申请人：Parion Sciences, Inc.
公开号：US20140171447A1
公开（公告）日：2014-06-19
This invention provides compounds of the formula I:
and their pharmaceutically acceptable salts, useful as sodium channel blockers, compositions containing the same, therapeutic methods and uses for the same and processes for preparing the same.
[EN] COMPOUNDS AND THEIR USE AS BACE INHIBITORS<br/>[FR] COMPOSÉS ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE BACE
申请人：ASTRAZENECA AB
公开号：WO2016055858A1
公开（公告）日：2016-04-14
The present application relates to compounds of formula (I), (la), or (lb) and their pharmaceutical compositions/preparations. This application further relates to methods of treating or preventing Αβ-related pathologies such as Down's syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease.
[EN] METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS<br/>[FR] MÉTHYLOXAZOLES ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE
申请人：MERCK SHARP & DOHME
公开号：WO2016089721A1
公开（公告）日：2016-06-09
The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.
N-PHENYL-1,1,1-TRIFLUOROMETHANESULFONAMIDE HYDRAZONE DERIVATIVE COMPOUNDS AND THEIR USAGE IN CONTROLLING PARASITES
申请人：Winzenberg Norman Kevin
公开号：US20070238700A1
公开（公告）日：2007-10-11
Novel N-phenyl-1,1,1-trifluoromethanesulfonamide compounds useful for controlling endo and/or ectoparasites in the environment are provided, together with methods of making the same, and methods of using the inventive compounds to treat parasite infestations in vivo and ex vivo.
