Paroxetine metabolism occurs in the liver and is largely mediated by cytochrome CYP2D6 with contributions from CYP3A4 and possibly other cytochrome enzymes. Genetic polymorphisms of the CYP2D6 enzyme may alter the pharmacokinetics of this drug. Poor metabolizers may demonstrate increased adverse effects while rapid metabolizers may experience decreased therapeutic effects. The majority of a paroxetine dose is oxidized to a catechol metabolite that is subsequently converted to both glucuronide and sulfate metabolites via methylation and conjugation. In rat synaptosomes, the glucuronide and sulfate conjugates have been shown to thousands of times less potent than paroxetine itself. The metabolites of paroxetine are considered inactive.
The exact metabolic fate of paroxetine has not been fully elucidated; however, paroxetine is extensively metabolized, probably in the liver. The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared by the body. Conjugates with glucuronic acid and sulfate predominate, and the principal metabolites have been isolated and identified. The metabolites of paroxetine have been shown to possess no more than 2% of the potency of the parent compound as inhibitors of serotonin reuptake; therefore, they are essentially inactive.
Paroxetine is extensively metabolized after oral administration. The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared. Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug interactions
Paroxetine is extensively metabolized after oral administration, likely in the liver. The main metabolites are polar and conjugated products of oxidation and methylation, which are readily eliminated by the body. The predominant metabolites are glucuronic acid and sulfate conjugates. Paroxetine metabolites do not possess significant pharmacologic activity (less than 2% that of parent compound). Paroxetine is metabolized by cytochrome P450 (CYP) 2D6. Enzyme saturation appears to account for the nonlinear pharmacokinetics observed with increasing dose and duration of therapy.
Route of Elimination: Approximately 64% of a 30 mg oral solution of paroxetine was excreted in the urine with 2% as the parent compound and 62% as metabolites. Approximately 36% of the dose was excreted in the feces (via bile), mostly as metabolites and less than 1% as parent compound.
Half Life: 21-24 hours
IDENTIFICATION AND USE: Paroxetine is an odorless off-white powder formulated into an oral suspension, extended-release film-coated tablets, or film-coated tablets. Paroxetine a second generation selective serotonin-reuptake inhibitor is used for the treatment of major depressive disorder, obsessive and compulsive disorder, panic disorder, social anxiety disorders, general anxiety disorders, and posttraumatic stress disorder. Paroxetine has more recently been approved for use in the treatment of moderate to severe vasomotor symptoms (VMS) associated with menopause. HUMAN EXPOSURE AND TOXICITY: Spontaneous cases of deliberate or accidental overdosage during paroxetine treatment have been reported; some of these cases were fatal and some of the fatalities appeared to involve paroxetine alone. Commonly reported adverse reactions associated with paroxetine overdosage include somnolence, coma, nausea, tremor, tachycardia, confusion, vomiting, and dizziness. Other notable signs and symptoms observed with overdoses involving paroxetine (alone or with other substances) include mydriasis, convulsions (including status epilepticus), ventricular dysrhythmias (including torsades de pointes), hypertension, aggressive reactions, syncope, hypotension, stupor, bradycardia, dystonia, rhabdomyolysis, symptoms of hepatic dysfunction (hepatic failure, hepatic necrosis, jaundice, hepatitis, and hepatic steatosis), serotonin syndrome, manic reactions, myoclonus, acute renal failure, and urinary retention. During premarketing testing, seizures occurred in 0.1% of patients treated with paroxetine. During premarketing testing, hypomania or mania occurred in approximately 1.0% of paroxetine-treated unipolar patients. In a subset of patients classified as bipolar, the rate of manic episodes was 2.2% for paroxetine and 11.6% for the combined active-control groups. Stevens-Johnson syndrome and toxic epidermal necrolysis have also been reported in paroxetine-treated patients. Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of congenital malformations, particularly cardiovascular malformations. Perinatal adverse effects, including respiratory distress and neonatal adaptation problems are common in exposed infants, and an increased risk for persistent pulmonary hypertension of the newborn (PPHN) has been observed. Also, some neonates exposed to paroxetine and other selective serotonin-reuptake inhibitors (SSRIs) or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) late in the third trimester of pregnancy have developed complications that occasionally have been severe and required prolonged hospitalization, respiratory support, enteral nutrition, and other forms of supportive care in special care nurseries. Clinical findings reported to date in the neonates have included respiratory distress, cyanosis, apnea, seizures, temperature instability or fever, feeding difficulty, dehydration, excessive weight loss, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, reduced or lack of reaction to pain stimuli, and constant crying. Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Genotoxicity tests for cytogenetic aberrations in vitro in human lymphocytes were negative. ANIMAL STUDIES: Two-year carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and 25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). There was a significantly greater number of male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and 4/50 for control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear trend across dose groups for the occurrence of lymphoreticular tumors in male rats. Female rats were not affected. Although there was a dose-related increase in the number of tumors in mice, there was no drug-related increase in the number of mice with tumors. The relevance of these findings to humans is unknown. Reproduction studies in rats receiving oral paroxetine dosages of 50 mg/kg daily and in rabbits receiving 6 mg/kg daily during organogenesis have been conducted. Although these studies have not revealed evidence of teratogenicity, an increase in pup deaths was observed in rats during the first 4 days of lactation when dosing occurred during the last trimester of gestation and continued throughout lactation. This effect occurred at a dose of 1 mg/kg daily. A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of 15 mg/kg/day. Irreversible lesions occurred in the reproductive tract of male rats after dosing in toxicity studies for 2 to 52 weeks. These lesions consisted of vacuolation of epididymal tubular epithelium at 50 mg/kg/day and atrophic changes in the seminiferous tubules of the testes with arrested spermatogenesis at 25 mg/kg/day. Paroxetine produced no genotoxic effects in a battery of in vitro and in vivo assays that included the following: Bacterial mutation assay, mouse lymphoma mutation assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse bone marrow and in a dominant lethal test in rats.
Paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake. Paroxetine likely inhibits the reuptake of serotonin at the neuronal membrane, enhances serotonergic neurotransmission by reducing turnover of the neurotransmitter, therefore it prolongs its activity at synaptic receptor sites and potentiates 5-HT in the CNS; paroxetine is more potent than both sertraline and fluoxetine in its ability to inhibit 5-HT reuptake. Compared to the tricyclic antidepressants, SSRIs have dramatically decreased binding to histamine, acetylcholine, and norepinephrine receptors. The mechanism of action for the treatment of vasomotor symptoms is unknown.
Liver test abnormalities have been reported to occur in up to 1% of patients on paroxetine, but elevations are usually modest and usually do not require dose modification or discontinuation. Rare instances of acute, clinically apparent episodes of liver injury, with marked liver enzyme elevations with or without jaundice, have been reported in patients on paroxetine. The onset of injury is usually within 2 to 16 weeks, but can be more delayed, to up to 1 year. The pattern of serum enzyme elevations varies from hepatocellular to mixed or cholestatic. While most cases are mild-to-moderate in severity, severe cases with hepatic failure have been reported. Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) are uncommon.
Paroxetine is readily absorbed from the gastrointestinal tract. Due to the first-pass metabolism, the bioavailability ranges from 30-60%. Cmax is attained 2 to 8 hours after an oral dose. Mean Tmax is 4.3 hours in healthy patients. The steady-state concentration of paroxetine is achieved within 7 to 14 days of oral therapy. In a pharmacokinetic study, AUC in healthy patients was 574 ng·h/mL and 1053 ng·h/mL in those with moderate renal impairment.
About 2/3 of a single paroxetine dose is found to be excreted in the urine and the remainder is found to be excreted in feces. Almost all of the dose is eliminated as metabolites; 3% is found to be excreted as unchanged paroxetine. About 64% of a 30 mg oral dose was found excreted in the urine, with 2% as the parent drug and 62% appearing as metabolites. Approximately 36% of the dose was found to be eliminated in the feces primarily as metabolites and less than 1% as the parent compound.
Paroxetine has a large volume of distribution and is found throughout the body, including in the central nervous system. Only 1% of the drug is found in the plasma. Paroxetine is found in the breast milk at concentrations similar to the concentrations found in plasma.
The apparent oral clearance of paroxetine is 167 L/h. The clearance of paroxetine in patients with renal failure is significantly lower and dose adjustment may be required, despite the fact that it is mainly cleared by the liver. Dose adjustments may be required in hepatic impairment.
Paroxetine hydrochloride appears to be slowly but well absorbed from the GI tract following oral administration. Although the oral bioavailability of paroxetine hydrochloride in humans has not been fully elucidated to date, the manufacturer states that paroxetine is completely absorbed after oral dosing of a solution of the hydrochloride salt. However, the relative proportion of an oral dose that reaches systemic circulation unchanged appears to be relatively small because paroxetine undergoes extensive first-pass metabolism. The oral tablets and suspension of paroxetine hydrochloride reportedly are bioequivalent.
Bis(3,4-methylenedioxy-6-[(3S,4R)-4-(4-fluorophenyl)piperidine-3-ylmethoxy]methane DiHydrochloride; 3,3'-[Methylenebis(1,3-benzodioxole-6,5-diyloxymethylene)]bis [4-(4-fluorophenyl)piperidine DiHydrochloride; Paroxetine EP Impurity F
[EN] AZA PYRIDONE ANALOGS USEFUL AS MELANIN CONCENTRATING HORMONE RECEPTOR-1 ANTAGONISTS<br/>[FR] ANALOGUES D'AZAPYRIDONE UTILES COMME ANTAGONISTES DU RÉCEPTEUR 1 DE L'HORMONE CONCENTRANT LA MÉLANINE
申请人：BRISTOL MYERS SQUIBB CO
公开号：WO2010104818A1
公开（公告）日：2010-09-16
MCHR1 antagonists are provided having the following Formula (I): A1 and A2 are independently C or N; E is C or N; Q1, Q2, and Q3 are independently C or N provided that at least one of Q1, Q2, and Q3 is N but not more than one of Q1, Q2, and Q3 is N; D1 is a bond, -CR8R9 X-, -XCR8R9-, -CHR8CHR9-, -CR10=CR10'-, -C≡C-, or 1,2-cyclopropyl; X is O, S or NR11; R1, R2, and R3 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, lower cycloalkyl, -CF3, -OCF3, -OR12 and -SR12; G is O, S or -NR15; D2 is lower alkyl, lower cycloalkyl, lower alkylcycloalkyl, lower cycloalkylalkyl, lower cycloalkoxyalkyl or lower alkylcycloalkoxy or when G is NR15, G and D2 together may optionally form an azetidine, pyrrolidine or piperidine ring; Z1 and Z2 are independently hydrogen, lower alkyl, lower cycloalkyl, lower alkoxy, lower cycloalkoxy, halo, -CF3, -OCONR14R14', -CN, -CONR14R14', -SOR12, -SO2R12, -NR14COR14', -NR14CO2R14', -CO2R12, NR14SO2R12 or COR12; R5, R6, and R7 are independently selected from the group consisting of hydrogen lower alkyl, lower cycloalkyl, -CF3, -SR12, lower alkoxy, lower cycloalkoxy, -CN, -CONR14R14', SOR12, SO2R12, NR14COR14', NR14CO2R12, CO2R12, NR14SO2R12 and -COR12; R8, R9, R10, R10', R11 are independently hydrogen or lower alkyl; R12 is lower alkyl or lower cycloalkyl; R14 and R14' are independently H, lower alkyl, lower cycloalkyl or R14 and R14' together with the N to which they are attached form a ring having 4 to 7 atoms; and R15 is independently selected from the group consisting of hydrogen and lower alkyl. Such compounds are useful for the treatment of MCHR1 mediated diseases, such as obesity, diabetes, IBD, depression, and anxiety.
[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.
New Drug Delivery System for Crossing the Blood Brain Barrier
申请人：Lipshutz H. Bruce
公开号：US20070203080A1
公开（公告）日：2007-08-30
New ubiquinol analogs are disclosed, as well as methods of using these compounds to deliver drug moieties to the body.
新的泛醌类似物被披露，以及利用这些化合物将药物基团输送到人体的方法。
[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.
4' SUBSTITUTED COMPOUNDS HAVING 5-HT6 RECEPTOR AFFINITY
申请人：Dunn Robert
公开号：US20080318941A1
公开（公告）日：2008-12-25
The present disclosure provides compounds having affinity for the 5-HT
6
receptor which are of the formula (I):
wherein R
1
, R
2
, R
5
, R
6
, B, D, E, G, Q, x and n are as defined herein. The disclosure also relates to methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
