Oxcarbazepine is rapidly and extensively metabolized to its primary metabolite, MHD, which is responsible for the bulk of its anti-epileptic activity and exists in much higher concentrations in the plasma than the parent drug. MHD is formed via reduction by several members of the aldo-keto reductase family of cytosolic liver enzymes and exists as a racemate in plasma in an approximate ratio of 80% (S)-MHD to 20% (R)-MHD. MHD is further metabolized to glucuronide conjugate metabolites for excretion, and small amounts are oxidized to 10-,11-dihydro-10,11-dihydroxycarbamazepine (DHD) which is pharmacologically inactive. Only 10% of an administered dose of oxcarbazepine will remain as either the parent drug or glucuronide conjugates of the parent drug.
Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to its 10-monohydroxy metabolite, MHD, which is primarily responsible for the pharmacological effect of Trileptal. MHD is metabolized further by conjugation with glucuronic acid. Minor amounts (4% of the dose) are oxidized to the pharmacologically inactive 10,11-dihydroxy metabolite (DHD). Oxcarbazepine is cleared from the body mostly in the form of metabolites which are predominantly excreted by the kidneys. More than 95% of the dose appears in the urine, with less than 1% as unchanged oxcarbazepine. Fecal excretion accounts for less than 4% of the administered dose. Approximately 80% of the dose is excreted in the urine either as glucuronides of MHD (49%) or as unchanged MHD (27%); the inactive DHD accounts for approximately 3% and conjugates of MHD and oxcarbazepine account for 13% of the dose.
The disposition of the new anti-epileptic agent oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide) has been studied in two healthy volunteers following an oral 400 mg dose of (14)C-labelled drug. The dose was excreted almost completely in the urine (94.6 and 97.1%) within six days. Fecal excretion amounted to 4.3 and 1.9% of the dose in the two subjects. In the 0-6 days urine samples the biotransformation products have been isolated and identified. 10,11-Dihydro-10-hydroxycarbamazepine (GP 47,779) and its two diastereoisomeric O-glucuronides were found as main metabolites. Taken together, they accounted for 79% of urinary (14)C. Unchanged oxcarbazepine, and its sulfate and glucuronide conjugates were isolated in smaller amounts only (13%). Other minor metabolites were the trans- and cis-isomers of 10,11-dihydro-10,11-dihydroxy-carbamazepine (approximately 4%), and a phenolic derivative of GP 47,779 (less than 1%). The biotransformation of oxcarbazepine proceeds mainly by reduction to GP 47,779, and subsequent conjugation with glucuronic acid. Reduction is stereospecific, favoring the S-configuration of GP 47,779. Direct conjugation of oxcarbazepine, in the enol form, is a minor pathway. Oxidative reactions are unimportant.
... The interaction potential of oxcarbazepine is relatively low. However, enzyme-inducing antiepileptic drugs such as phenytoin, phenobarbital or carbamazepine can reduce slightly the concentrations of 10,11-dihydro-10-hydroxy-carbazepine (monohydroxy derivative, MHD). Verapamil may moderately decrease MHD concentrations, but this effect is probably without clinical relevance. The influence of oxcarbazepine on other antiepileptic drugs is not clinically relevant in most cases. However, oxcarbazepine appears to increase concentrations of phenytoin and to decrease trough concentrations of lamotrigine and topiramate. Oxcarbazepine lowers concentrations of ethinylestradiol and levonorgestrel, and women treated with oxcarbazepine should consider additional contraceptive measures. Due to the absent or lower enzyme-inducing effect of oxcarbazepine, switching from carbamazepine to oxcarbazepine can result in increased serum concentrations of comedication, sometimes associated with adverse effects. ...
Oxcarbazepine is completely absorbed and extensively metabolized to its pharmacologically active 10-monohydroxy metabolite (MHD) by cytosolic enzymes. MHD is metabolized further by conjugation with glucuronic acid.
Route of Elimination: Oxcarbazepine is cleared from the body mostly in the form of metabolites which are predominantly excreted by the kidneys. Fecal excretion accounts for less than 4% of the administered dose.
Half Life: The half-life of the parent is about 2 hours, while the half-life of MHD is about 9 hours, so that MHD is responsible for most anti-epileptic activity.
The exact mechanism by which oxcarbazepine exerts its anticonvulsant effect is unknown. It is known that the pharmacological activity of oxcarbazepine occurs primarily through its 10-monohydroxy metabolite (MHD). In vitro studies indicate an MHD-induced blockade of voltage-sensitive sodium channels, resulting in stabilization of hyperexcited neuronal membranes, inhibition of repetitive neuronal discharges, and diminution of propagation of synaptic impulses.
Chronic therapy with oxcarbazepine is associated with elevations in serum aminotransferase levels in a small proportion of patients. These elevations are rarely clinically significant and do not usually require dose modification. Clinically apparent hepatotoxicity from oxcarbazepine is uncommon but described, and is less common than occurs with carbamazepine. Oxcarbazepine hepatotoxicity usually arises in the setting of anticonvulsant hypersensitivity syndrome with onset of fever, followed by rash, facial edema, lymphadenopathy, elevations in white count and eosinophilia 2 to 8 weeks after starting therapy. The liver involvement ranges from a mild and transient elevation in serum enzymes to abrupt onset of an acute hepatitis-like syndrome, that can be severe and even fatal. The typical enzyme elevations are usually mixed, but can be either hepatocellular or cholestatic. Liver biopsy shows mixed necroinflammatory-cholestatic injury with prominence of eosinophils and occasionally granulomas.
Oxcarbazepine is completely absorbed following oral administration. A single 600mg dose of oxcarbazepine resulted in an MHD Cmax of 34 μmol/L and a median Tmax of 4.5 hours. When administered twice daily, steady-state levels of MHD are attained within 2-3 days. The rate and extent of absorption of oxcarbazepine is not affected by food intake.
Following oral administration, more than 95% of the administered dose of oxcarbazepine is found in the urine. Of this, approximately 49% is MHD glucuronide metabolites, 27% is unchanged MHD, 3% is inactive DHD metabolites, 13% is conjugated oxcarbazepine, and less than 1% is unchanged parent drug. Fecal elimination accounts for only 4% of the administered dose.
The apparent volume of distribution of oxcarbazepine is 49 L. The apparent volumes of distribution of (S)- and (R)-MHD were found to be 23.6 L and 31.7 L, respectively.
Plasma clearance of oxcarbazepine has been estimated to be approximately 84.9 L/h, whereas plasma clearance of its active metabolite, MHD, was estimated to be 2.0 L/h. Rapid metabolic clearance appears to be the main pathway for oxcarbazepine, while clearance of its metabolites occurs mainly via renal excretion.
来源:DrugBank
吸收、分配和排泄
奥卡西平完全被吸收。食物不会改变奥卡西平的吸收速率和程度。
Oxcarbazepine is completely absorbed. Food does not alter the rate and extent of absorption of oxcarbazepine.
Anticonvulsant and Sodium Channel-Blocking Properties of Novel 10,11-Dihydro-5H-dibenz[b,f]azepine-5-carboxamide Derivatives
摘要：
A. series of esters of the major metabolite of oxcarbazepine (2), 10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide, were synthesized and evaluated for their anticonvulsant and brain sodium channel-blocking properties. The compounds were assayed intraperitoneally and per os in rats against seizures induced by maximal electroshock (MES). Neurologic deficit was evaluated by the rotarod test. The enantiomeric acetates (R)-11 and (S)-12 were the most active of the series against MES-induced seizures with oral ED50 values at t(max) of 10.9 +/- 2.3 and 4.7 +/- 9 mg/kg, respectively. After intraperitoneal administration, carbamazepine (1) behaved more potently than 2 and all other new dibenz[b,f]azepine-5-carboxamide derivatives in the MES test; compounds 2 and 12 were equally potent. In the rotarod test, low doses of 1. produced considerable motor impairment, which did not occur with 2, enantiomeric alcohols (S)-6;, (R)-7, and racemic alcohol, or racemic acetate 10 or (R)-11. The potencies of the racemic and enantiomerically pure alcohols 8, (S)-6, and (R)-7 derived from 2 in the MES and rotarod test were found to be similar between them, and consequently they exhibit similar protective index values. All three forms of the alcohol and their corresponding acetates (pairs 8 & 10, 6 & 12, and 7 & 11) were found to differ in the MES or rotarod tests; the ED50 value for (S)-6 against MES-induced seizures was nearly 3-fold that for (S)-12. The protective index also differed markedly between all stereoisomers of the alcohol and their corresponding acetates, most pronouncedly for compound (S)-12 which attained the highest value (12.5) among all compounds tested. Blockade of voltage-sensitive sodium channels was studied by investigating [H-3]-batrachotoxinin A 20-alpha-benzoate ([H-3]BTX) binding. Acetates (R)-11 and (S)-12 were more potent than the standards 1 and-2 at inhibiting the binding of [H-3]BTX to sodium channels and the influx: of Na-22(+) into rat brain synaptosomes. It is concluded that acetates (R)-11 and (5)-12 are not simple metabolic precursors of alcohols (R)-7 and (S)-6 in rodents but that they possess anticonvulsant and sodium channel-blocking properties in their own right.
[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.
Amino-substituted heterocycles, compositions thereof, and methods of treatment therewith
申请人：D'Sidocky Neil R.
公开号：US20080242694A1
公开（公告）日：2008-10-02
Provided herein are Heterocyclic Compounds having the following structure:
wherein R
1
, R
2
, X, Y and Z are as defined herein, compositions comprising an effective amount of a Heterocyclic Compound and methods for treating or preventing cancer, inflammatory conditions, immunological conditions, metabolic conditions and conditions treatable or preventable by inhibition of a kinase pathway comprising administering an effective amount of a Heterocyclic Compound to a patient in need thereof.
[EN] PROCESSES USEFUL FOR THE SYNTHESIS OF (R)-1-{2-[4'-(3-METHOXYPROPANE-1-SULFONYL)-BIPHENYL-4-YL]-ETHYL}-2-METHYL-PYRROLIDINE<br/>[FR] PROCÉDÉS UTILES POUR LA SYNTHÈSE DE LA (R)-1-{2-[4'-(3-MÉTHOXYPROPANE-1-SULFONYL)-BIPHÉNYL-4-YL]-ÉTHYL}-2-MÉTHYL-PYRROLIDINE
申请人：ARENA PHARM INC
公开号：WO2009128907A1
公开（公告）日：2009-10-22
Processes useful for making a pharmaceutically useful compound according to Formula (I), forms of such a compound, and intermediates useful in such processes are described.
根据公式（I）制备药用化合物的有用过程，以及该化合物的形式和在这些过程中有用的中间体被描述。
[EN] AGENT FOR PREVENTING OR TREATING NEUROPATHY<br/>[FR] AGENT POUR LA PRÉVENTION OU LE TRAITEMENT DE NEUROPATHIE
申请人：TAKEDA CHEMICAL INDUSTRIES LTD
公开号：WO2004039365A1
公开（公告）日：2004-05-13
The present invention provides an agent for preventing or treating neuropathy having superior action and low toxicity. This agent comprises a compound represented by the formula:wherein ring A is a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may further have substituent(s);B is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;X is a divalent acyclic hydrocarbon group;Z is -O-, -S-, -NR2-, -CONR2- or -NR2CO- (R2 is a hydrogen atom or an optionally substituted alkyl group);Y is a bond or a divalent acyclic hydrocarbon group;R1 is an optionally substituted cyclic group, an optionally substituted amino group or an optionally substituted acyl group, provided that when the 5-membered aromatic heterocycle represented by ring A is imidazole, then Z should not be -O-, or a salt thereof.
[EN] IMIDAZOPYRIDINE COMPOUNDS AND USES THEREOF<br/>[FR] COMPOSÉS IMIDAZOPYRIDINE ET LEURS UTILISATIONS
申请人：NEOMED INST
公开号：WO2014117274A1
公开（公告）日：2014-08-07
This invention generally relates to substituted imidazopyridine compounds, particularly substituted 4-(imidazo[1,2-a]pyridin-2-yl)benzamide compounds and salts thereof. This invention also relates to pharmaceutical compositions and kits comprising such a compound, uses of such a compound (including, for example, treatment methods and medicament preparations), processes for making such a compound, and intermediates used in such processes.
