Lorcaserin has extensive hepatic metabolism producing inactive compounds. Lorcaserin sulfamate (M1) is the major metabolite circulating in the plasma, and N-carbamoyl glucuronide lorcaserin (M5) is the major metabolite in urine. Other minor metabolites that are both excreted in urine are glucuronide or sulfate conjugates.
Lorcaserin is extensively metabolized by the liver and the metabolites are excreted in the urine. In a human mass balance study in which healthy subjects ingested radiolabeled lorcaserin, 94.5% of radiolabeled material was recovered, with 92.3% and 2.2% recovered from urine and feces, respectively.
Lorcaserin is extensively metabolized in the liver by multiple enzymatic pathways. After oral administration of Belviq, the major circulating metabolite is lorcaserin sulfamate (M1), with a plasma Cmax that exceeds lorcaserin Cmax by 1- to 5-fold. N-carbamoyl glucuronide lorcaserin (M5) is the major metabolite in urine; M1 is a minor metabolite in urine, representing approximately 3% of dose. Other minor metabolites excreted in urine were identified as glucuronide or sulfate conjugates of oxidative metabolites. The principal metabolites exert no pharmacological activity at serotonin receptors.
Lorcaserin, a selective serotonin 5-hydroxytryptamine 2C receptor agonist, is being developed for weight management. The oxidative metabolism of lorcaserin, mediated by recombinant human cytochrome P450 (P450) and flavin-containing monooxygenase (FMO) enzymes, was examined in vitro to identify the enzymes involved in the generation of its primary oxidative metabolites, N-hydroxylorcaserin, 7-hydroxylorcaserin, 5-hydroxylorcaserin, and 1-hydroxylorcaserin. Human CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2D6, CYP3A4, and FMO1 are major enzymes involved in N-hydroxylorcaserin; CYP2D6 and CYP3A4 are enzymes involved in 7-hydroxylorcaserin; CYP1A1, CYP1A2, CYP2D6, and CYP3A4 are enzymes involved in 5-hydroxylorcaserin; and CYP3A4 is an enzyme involved in 1-hydroxylorcaserin formation. In 16 individual human liver microsomal preparations (HLM), formation of N-hydroxylorcaserin was correlated with CYP2B6, 7-hydroxylorcaserin was correlated with CYP2D6, 5-hydroxylorcaserin was correlated with CYP1A2 and CYP3A4, and 1-hydroxylorcaserin was correlated with CYP3A4 activity at 10.0 uM lorcaserin. No correlation was observed for N-hydroxylorcaserin with any P450 marker substrate activity at 1.0 uM lorcaserin. N-Hydroxylorcaserin formation was not inhibited by CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2D6, and CYP3A4 inhibitors at the highest concentration tested. Furafylline, quinidine, and ketoconazole, selective inhibitors of CYP1A2, CYP2D6, and CYP3A4, respectively, inhibited 5-hydroxylorcaserin (IC(50) = 1.914 uM), 7-hydroxylorcaserin (IC(50) = 0.213 uM), and 1-hydroxylorcaserin formation (IC(50) = 0.281 uM), respectively. N-Hydroxylorcaserin showed low and high K(m) components in HLM and 7-hydroxylorcaserin showed lower K(m) than 5-hydroxylorcaserin and 1-hydroxylorcaserin in HLM. The highest intrinsic clearance was observed for N-hydroxylorcaserin, followed by 7-hydroxylorcaserin, 5-hydroxylorcaserin, and 1-hydroxylorcaserin in HLM. Multiple human P450 and FMO enzymes catalyze the formation of four primary oxidative metabolites of lorcaserin, suggesting that lorcaserin has a low probability of drug-drug interactions by concomitant medications.
Lorcaserin, a selective serotonin 5-HT(2C) receptor agonist, is a weight management agent in clinical development. Lorcaserin N-carbamoyl glucuronidation governs the predominant excretory pathway of lorcaserin in humans. Human UDP-glucuronosyltransferases (UGTs) responsible for lorcaserin N-carbamoyl glucuronidation are identified herein. Lorcaserin N-carbamoyl glucuronide formation was characterized by the following approaches: metabolic screening using human tissues (liver, kidney, intestine, and lung) and recombinant enzymes, kinetic analyses, and inhibition studies. Whereas microsomes from all human tissues studied herein were found to be catalytically active for lorcaserin N-carbamoyl glucuronidation, liver microsomes were the most efficient. With recombinant UGT enzymes, lorcaserin N-carbamoyl glucuronidation was predominantly catalyzed by three UGT2Bs (UGT2B7, UGT2B15, and UGT2B17), whereas two UGT1As (UGT1A6 and UGT1A9) played a minor role. UGT2B15 was most efficient, with an apparent K(m) value of 51.6 + or - 1.9 uM and V(max) value of 237.4 + or - 2.8 pmol/mg protein/min. The rank order of catalytic efficiency of human UGT enzymes for lorcaserin N-carbamoyl glucuronidation was UGT2B15 > UGT2B7 > UGT2B17 > UGT1A9 > UGT1A6. Inhibition of lorcaserin N-carbamoyl glucuronidation activities of UGT2B7, UGT2B15, and UGT2B17 in human liver microsomes by mefenamic acid, bisphenol A, and eugenol further substantiated the involvement of these UGT2B isoforms. In conclusion, multiple human UGT enzymes catalyze N-carbamoyl glucuronidation of lorcaserin; therefore, it is unlikely that inhibition of any one of these UGT activities will lead to significant inhibition of the lorcaserin N-carbamoyl glucuronidation pathway. Thus, the potential for drug-drug interaction by concomitant administration of a drug(s) that is metabolized by any of these UGTs is remote.
In premarketing clinical trials, serum aminotransferase elevations were no more common among patients receiving lorcaserin than placebo. Clinically apparent liver injury due to lorcaserin has not been reported, but the numbers of patients treated has been limited.
Weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with insulin and/or insulin secretagogues (e.g., sulfonylureas); hypoglycemia was observed in clinical trials with Belviq. Belviq has not been studied in combination with insulin. Measurement of blood glucose levels prior to starting Belviq and during Belviq treatment is recommended in patients with type 2 diabetes. Decreases in medication doses for anti-diabetic medications which are non-glucose-dependent should be considered to mitigate the risk of hypoglycemia. If a patient develops hypoglycemia after starting Belviq, appropriate changes should be made to the anti-diabetic drug regimen.
Based on the mechanism of action of Belviq and the theoretical potential for serotonin syndrome, use with extreme caution in combination with other drugs that may affect the serotonergic neurotransmitter systems, including, but not limited to, triptans, monoamine oxidase inhibitors (MAOIs, including linezolid, an antibiotic which is a reversible non-selective MAOI), selective serotonin reuptake inhibitors (SSRIs), selective serotonin-norepinephrine reuptake inhibitors (SNRIs), dextromethorphan, tricyclic antidepressants (TCAs), bupropion, lithium, tramadol, tryptophan, and St. John's Wort.
Belviq should not be used in combination with serotonergic and dopaminergic drugs that are potent 5-HT2B receptor agonists and are known to increase the risk for cardiac valvulopathy (e.g., cabergoline).
Treatment of overdose should consist of Belviq discontinuation and general supportive measures in the management of overdosage. Belviq is not eliminated to a therapeutically significant degree by hemodialysis.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
吸收
洛卡塞林大约在1.5到2小时达到血浆峰值浓度，但其生物利用度尚未确定。
Lorcaserin has a peak plasma concentration of about 1.5 - 2 hours, but the bioavailability was not determined.
来源:DrugBank
吸收、分配和排泄
消除途径
洛卡塞林通过肝脏代谢消除，其代谢物大部分通过尿液（92.3%）排出，少量通过粪便（2.2%）排出。
Lorcaserin is eliminated by hepatic metabolism, and the metabolites are eliminated mostly in the urine (92.3%) and some through feces (2.2%).
来源:DrugBank
吸收、分配和排泄
分布容积
分布容积未确定，但洛卡塞林会分布到中枢神经系统和脑脊液中。
The volume of distribution was not determined, but lorcaserin distributes to the central nervous system and cerebrospinal fluid.
Lorcaserin distributes to the cerebrospinal fluid and central nervous system in humans. Lorcaserin hydrochloride is moderately bound (approximately 70%) to human plasma proteins.
Novel phenyl-substituted imidazolidines, process for preparation thereof, medicaments comprising said compounds and use thereof
申请人：JAEHNE Gerhard
公开号：US20110178134A1
公开（公告）日：2011-07-21
The invention relates to compounds of formula (I) wherein the groups have stated meanings, and to their physiologically compatible salts. Said compounds are suitable, for example, as anti-obesity drugs and for treating cardiometabolic syndrome.
AZOLOPYRIDIN-3-ONE DERIVATIVES AS INHIBITORS OF LIPASES AND PHOSPHOLIPASES
申请人：Petry Stefan
公开号：US20130157941A1
公开（公告）日：2013-06-20
The present invention relates to azolopyridin-3-one derivatives of the general formula (I) with the meanings specified in the description, to their pharmaceutically usable salts and to their use as drug substances.
Arylchalcogenoarylalkyl-substituted imidazolidine-2,4-diones, process for preparation thereof, medicaments comprising these compounds and use thereof
申请人：JAEHNE Gerhard
公开号：US20110053947A1
公开（公告）日：2011-03-03
The invention relates to compounds of formula (I) wherein the groups R and R′, A, D, E, G, L, p and R1 to R10 have the stated meanings and to their physiologically compatible salts. Said compounds are suitable, for example, as anti-obesity drugs.
Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, process for preparing them, medicaments comprising these compounds, and their use
申请人：JAEHNE Gerhard
公开号：US20090215728A1
公开（公告）日：2009-08-27
This invention relates to arylaminoaryl-alkyl-substituted imidazolidone-2,4-diones of formula (I) and also to their physiologically tolerated salts:
Wherein R, R′, R1 to R10, A, D, E, G, L and p are as defined herein. The invention also relates to processes for preparing them, pharmaceutical compositions comprising them and their therapeutic use. The compounds are suitable, for example, as anti-obesity drugs and for treating cardiometabolic syndrome.
Novel aromatic fluoroglycoside derivatives, pharmaceuticals comprising said compounds and the use thereof
申请人：FRICK Wendelin
公开号：US20110059910A1
公开（公告）日：2011-03-10
The invention relates to substituted aromatic fluoroglycoside derivatives, and to the physiologically compatible salts and physiologically functional derivatives thereof. The invention also relates to methods of lowering blood sugar and the treatment of type I and type II diabetes.
