Metabolism is primarily via CYP3A4, slightly CYP2C19. Minimal involvement of CYP1A2, CYP2B6, CYP2C8, CYP2C9 or CYP2D6. At least 35 metabolites of flibanserin are produced, 2 of which reach plasma concentrations as high as parent drug, however they are pharmacologically inactive.
Flibanserin is primarily metabolized by CYP3A4 and, to a lesser extent, by CYP2C19. Based on in vitro and/or in vivo data, CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP2D6 contribute minimally to the metabolism of flibanserin. After a single oral solution dose of 50 mg 14C-radiolabeled flibanserin, 44% of the total 14C-flibanserin related radioactivity was recovered in urine, and 51% was recovered in feces. Flibanserin is extensively metabolized to at least 35 metabolites, most of them occurring in low concentrations in plasma. Two metabolites could be characterized that showed plasma concentrations similar to that achieved with flibanserin: 6,21-dihydroxy-flibanserin-6,21-disulfate and 6-hydroxy-flibanserin-6-sulfate. These two metabolites are inactive.
IDENTIFICATION AND USE: Flibanserin (trade name Addyi) is a non-hormonal drug approved for the treatment of generalized hypoactive sexual desire disorder (HSDD) in pre- and postmenopausal women. HUMAN EXPOSURE AND TOXICITY: The adverse event profile of flibanserin is similar to that of other centrally acting drugs. In human exposure studies, the most common reported adverse event was sedation/ drowsiness. Dizziness, nausea, fatigue and somnolence were also reported. Flibanserin can cause CNS depression. The use of flibanserin in patients with hepatic impairment increases flibanserin concentrations, which can cause severe hypotension and syncope. Hypotension and syncope are also an increased risk for patients taking moderate to strong CYP3A4 inhibitors. Concomitant alcohol use also increases the risk of severe hypotension and syncope in patients taking flibanserin. Flibanserin has preferential affinity for serotonin 5-HT(1A), dopamine D(4k), and serotonin 5-HT(2A) receptors. In vitro and in microiontophoresis, flibanserin behaves as a 5-HT(1A) agonist, a very weak partial agonist on dopamine D(4) receptors, and a 5-HT(2A) antagonist. Flibanserin does not display consistent effects in animal models of anxiety and seems to exert potential antipsychotic effects. Flibanserin may induce some sedation but does not induce observable toxic effects at pharmacologically relevant doses. ANIMAL STUDIES: In carcinogenicity studies, mammary tumors were observed in female mice. Hepatocellular carcinomas were reported in female and male mice, however, these effects were only noted in animals exposed to flibanserin at 3-10 x the clinically recommended dose.
In placebo controlled trials, liver test abnormalities were no more common with flibanserin than with placebo treatment, and what abnormalities occurred were mild and resolved spontaneously, usually without need for dose interruption. During these premarketing clinical trials and since its more widespread clinical availability, no instances of acute liver injury with jaundice have been reported attributable to flibanserin. However, the total clinical experience with flibanserin use has been limited. Many other serotonergic agents, such as the SSRIs, have been implicated in rare instances of clinically apparent liver injury. The latency to onset is typically 1 to 8 weeks and the pattern of enzyme elevations varies, ranging from cholestatic to hepatocellular. Mild signs and symptoms of hypersensitivity (rash, fever, eosinophilia) are common, but usually not prominent. Autoantibody formation is rare. The course is generally self-limited and mild-to-moderate in severity, but fatalities have been reported with some SSRIs. However, flibanserin itself has not been implicated in similar cases.
The concomitant use of Addyi with digoxin, a drug that is transported by P-glycoprotein (P-gp), increases the digoxin concentration. This may lead to digoxin toxicity.
In this study the functional interaction of the antidepressant drugs amitriptyline, mianserin, maprotiline, imipramine, fluoxetine and the putative antidepressant drug flibanserin has been studied on 5-HT7-mediated responses to 5-carboxamidotryptamine (5-CT) in the guinea-pig ileum. 5-CT induced a concentration-dependent inhibition of the contractile response to substance P (100 nM). Except for fluoxetine and flibanserin, all the antidepressants antagonized by different degrees the 5-CT inhibitory response with the following rank affinity order: mianserin > maprotiline > imipramine > amitriptyline. Mianserin was the only antidepressant to show a profile of competitive antagonism at 5-HT7 receptors in a tenfold range of concentrations (0.1-1 microM), with an affinity (pA2) value of 8.1 +/- 0.6. The antagonism of the other antidepressants was not concentration-dependent (amitriptyline) or was associated with slight or moderate reduction of the maximal 5-CT response (imipramine or maprotiline). The apparent affinity (pKB) values were: amitriptyline, 7.0 +/- 0.2; maprotiline, 7.3 +/- 0.6; imipramine, 7.2 +/- 0.4. Our results show that various +antidepressant drugs belonging to different chemical classes behave as antagonists at enteric 5-HT7 receptors through competitive or allosteric mechanisms. This evidence extends our previous findings demonstrating the interaction of antidepressants with other 5-HT receptors, namely 5-HT3 and 5-HT4 receptors.
The concomitant use of Addyi with CYP3A4 inducers substantially decreases flibanserin exposure compared to the use of Addyi alone. Examples of CYP3A4 inducers: Carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapetine, St. John's Wort.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
吸收
氟班色林绝对口服生物利用度为33%。
Flibanserin has an absolute oral availability of 33%.
来源:DrugBank
吸收、分配和排泄
消除途径
单次口服50毫克氟班色林溶液后，通过粪便（51%）和尿液（44%）排出。
Elimination via feces (51%) and urine (44%) following a single oral 50 mg dose of flibanserin solution.
来源:DrugBank
吸收、分配和排泄
大约98%的药物与人类血清蛋白结合，主要是与白蛋白结合。
Approximately 98% of the drug is bound to human serum proteins, mainly to albumin.
Food increased the extent of absorption and slowed the rate of absorption of a 50 mg dose of flibanserin (one half the recommended dosage). Low-, moderate-, and high-fat meals increased flibanserin AUC0-inf by 1.18-, 1.43-, and 1.56-fold; increased Cmax by 1.02-, 1.13-, and 1.15-fold; and prolonged median Tmax to 1.5, 0.9, 1.8 hours from 0.8 hours under fasted conditions, respectively.
Following oral ministration of a single 100 mg dose of flibanserin in healthy premenopausal women (N=8), mean (SD) Cmax was 419 (206) ng/mL and mean (SD) AUC0-inf was 1543 (511) ng*hr/mL. Median (range) time to reach Cmax was 0.75 (0.75 to 4.0) hours. Absolute bioavailability of flibanserin following oral dosing is 33%.
The present invention relates to a class of substituted purine compounds of formula (I), uses thereof, processes for the preparation thereof and compositions containing said compounds. These compounds have utility in a variety of therapeutic areas including sexual dysfunction.(I).
Compounds of formula (I) are disclosed. Compounds according to the and are useful for treating inflammation. Those compounds which are agonists are additionally useful for treating pain.
The present disclosure relates to compounds useful as inhibitors of the enzyme Fatty Acid Amide Hydrolase (FAAH). The disclosure also provides pharmaceutically acceptable compositions comprising the compounds of the disclosure and methods of using the compositions in the treatment or prevention of various disorders. Compounds of the invention are described in Table 1.
Sulfur(VI) fluoride compounds and methods for the preparation thereof
申请人：The Scripps Research Institute
公开号：US10117840B2
公开（公告）日：2018-11-06
This application describes a compound represented by Formula (I): (I) wherein: Y is a biologically active organic core group comprising one or more of an aryl group, a heteroaryl aryl group, a nonaromatic hydrocarbyl group, and a nonaromatic heterocyclic group, to which Z is covalently bonded; n is 1, 2, 3, 4 or 5; m is 1 or 2; Z is O, NR, or N; X1 is a covalent bond or —CH2CH2—, X2 is O or NR; and R comprises H or a substituted or unsubstituted group selected from an aryl group, a heteroaryl aryl group, a nonaromatic hydrocarbyl group, and a nonaromatic heterocyclic group. Methods of preparing the compounds, methods of using the compounds, and pharmaceutical compositions comprising the compounds are described as well.
The present invention relates to a class of melanocortin MCR4 agonists of general formula (I)
wherein R
1
, R
2
, R
3
, R
4
and R
5
are as defined herein and especially to selective MCR4 agonist compounds, to their use in medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes.
