Stable under recommended storage conditions. /Mefloquine hydrochloride/
解离常数：
pKa1 = 9.46 (amine); pKa2 = 13.79 (hydroxy) (est)
计算性质
辛醇/水分配系数(LogP)：
3.6
重原子数：
26
可旋转键数：
2
环数：
3.0
sp3杂化的碳原子比例：
0.47
拓扑面积：
45.2
氢给体数：
2
氢受体数：
9
ADMET
代谢
生物转化：肝脏（部分）；主要代谢为羧酸代谢物。
Biotransformation: Hepatic (partial); metabolized primarily to the carboxylic acid metabolite.
来源:Hazardous Substances Data Bank (HSDB)
代谢
Mefloquine is extensively metabolized in the liver by the cytochrome P450 system. In vitro and in vivo studies strongly suggested that CYP3A4 is the major isoform involved. Two metabolites of mefloquine have been identified in humans. The main metabolite, 2,8-bis-trifluoromethyl-4-quinoline carboxylic acid, is inactive in Plasmodium falciparum. In a study in healthy volunteers, the carboxylic acid metabolite appeared in plasma 2 to 4 hours after a single oral dose. Maximum plasma concentrations of the metabolite, which were about 50% higher than those of mefloquine, were reached after 2 weeks. Thereafter, plasma levels of the main metabolite and mefloquine declined at a similar rate. The area under the plasma concentration-time curve (AUC) of the main metabolite was 3 to 5 times larger than that of the parent drug. The other metabolite, an alcohol, was present in minute quantities only.
美氟奎在肝脏中被细胞色素P450系统广泛代谢。体外和体内研究强烈表明CYP3A4是主要的同种型。在人体中已经识别出两种美氟奎的代谢物。主要代谢物，2,8-双三氟甲基-4-喹啉羧酸，在恶性疟原虫中是无效的。在一项对健康志愿者的研究中，羧酸代谢物在单次口服剂量后2到4小时出现在血浆中。代谢物的最大血浆浓度，比美氟奎高出约50%，在2周后达到。此后，主要代谢物和美氟奎的血浆水平以相似的速度下降。主要代谢物的血浆浓度-时间曲线下面积（AUC）是母药物的3到5倍。另一种代谢物，一种醇，只存在于极少量。
Mefloquine is extensively metabolized in the liver by the cytochrome P450 system. In vitro and in vivo studies strongly suggested that CYP3A4 is the major isoform involved. Two metabolites of mefloquine have been identified in humans. The main metabolite, 2,8-bis-trifluoromethyl-4-quinoline carboxylic acid, is inactive in Plasmodium falciparum. In a study in healthy volunteers, the carboxylic acid metabolite appeared in plasma 2 to 4 hours after a single oral dose. Maximum plasma concentrations of the metabolite, which were about 50% higher than those of mefloquine, were reached after 2 weeks. Thereafter, plasma levels of the main metabolite and mefloquine declined at a similar rate. The area under the plasma concentration-time curve (AUC) of the main metabolite was 3 to 5 times larger than that of the parent drug. The other metabolite, an alcohol, was present in minute quantities only.
IDENTIFICATION AND USE: Mefloquine is a white or slightly yellow crystalline powder that is formulated into tablets. Mefloquine is an antimalarial agent which acts as a blood schizonticide. It is used for the prevention and treatment of malaria caused by strains of Plasmodium falciparum or P. vivax. HUMAN EXPOSURE AND TOXICITY: Overdosage of mefloquine produces manifestations that are similar to the adverse reactions reported with the drug. Vertigo, hallucinations, dizziness, nausea, hypotension, tachycardia, and seizures occurred in 2 patients who ingested an overdosage of mefloquine (up to 5250 mg over 5 days). Since seizures may also occur at therapeutic doses, mefloquine is contraindicated in patients with a history of seizures. Mefloquine has also been associated with neuropsychiatric manifestations: anxiety, paranoia, depression, hallucinations and psychotic behavior. These manifestations may continue long after mefloquine has been discontinued. These neuropsychiatric effects have been reported both after overdose and at therapeutic doses. To minimize the chance of these adverse effects, use of mefloquine for prophylaxis is contraindicated in patients with active depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia or other major psychiatric disorders. There is also evidence that the use of halofantrine during mefloqune therapy and within 15 weeks of the last dose of mefloquine increases the risk of a potential fatal prolongation of the corrected QT interval (QTc). This risk may also be increased following co-administration with ketoconazole. Clinically significant QTc interval prolongation has not been reported with mefloquine monotherapy. Several studies in pregnant women have shown no increase in the risk of teratogenic effects or adverse pregnancy outcomes following mefloquine treatment or prophylaxis during pregnancy. The WHO concluded however, that treatment with mefloquine should be undertaken cautiously during the first 12-14 weeks of gestation. ANIMAL STUDIES: While two year studies in mice and rats failed to show an increase in tumors, mefloquine did produce toxic effects. In one such study, rats were administered mefloquine in the diet at 0, 5, 12.5 or 30 mg/kg/day for 2 years. In the high dose group the weight gain of both sexes was significantly depressed and the incidence of spontaneous death was increased. Males had decreased testicle size and paralysis of hind limbs, while females showed increased vaginal hemorrhage, cystic ovaries and distended uteri filled with fluid. Elevated liver enzymes and blood urea nitrogen levels occurred for both sexes. At study completion, both sexes showed lesions in eye, lung, kidney, reproductive organs, skeletal muscle, spleen and lymph node. Retinal degeneration, opacity of the lens and/or retinal edema occurred at both the mid and high dose group. (Severity was greater in females). Mild lesions of reproductive organs and bile duct hyperplasia were seen in the mid dose group. Males had lesions in the epididymis and prostate; epithelial vacuolization of epididymis, foamy macrophages in lungs and skeletal muscle degeneration were observed in both sexes of the low dose group. The potential for mefloquine to cause neurological effects were investigated in 7-week-old female rats given a single oral dose of the drug. Potential mefloquine-induced neurological effects were monitored using a standard functional observational battery, automated open field tests, automated spontaneous activity monitoring, a beam traverse task, and histopathology. Mefloquine induced dose-related changes in endpoints associated with spontaneous activity and impairment of motor function and caused degeneration of specific brain stem nuclei (nucleus gracilis). Increased spontaneous motor activity was observed only during the rats' normal sleeping phase, suggesting a correlate to mefloquine-induced sleep disorders. Mefloquine was also shown to be teratogenic in mice, rats and rabbits. In one study, rats were administered mefloquine at doses up to 100 mg/kg/day by intragastric intubation. In the high dose group, rats grew slower and consumed less feed than controls. Fetuses had reduced body weight, reduced crown-rump length, increased incidence of externally visible soft tissue and skeletal defects; domes craniums occurred at a high rate, high incidence of hydrocephalus; malformed interparietals, incompletely ossified supra occipitals, and incompletely ossified skull bones were also observed. In a similar study in the mouse, mefloquine at doses of 100 and 200 mg/kg/day resulted in decreased body weight and a high incidence of cleft palate in fetuses. Mefloquine was also shown to impair fertility in both male and female rats. Mefloquine was not found to be mutagenic in the following tests: Ames Test, Fluctuation Test, Host (Mouse) Mediated Assay, Micronucleus Test, Induction of Point Mutations, Yeast Treat and Plate Test.
Chronic therapy with mefloquine is associated with asymptomatic, transient serum enzyme elevations in up to 18% of patients. These elevations are usually mild and resolve without dose modifications. Despite widespread use, mefloquine has rarely been linked to clinically apparent acute liver injury and too few reports are available to characterize the clinical features of such injury. Instances of acute hepatocellular injury as well as cholestatic hepatitis have been linked to use of mefloquine. Allergic manifestations (rash, fever, eosinophilia) and autoantibody formation are rare.
◉ Summary of Use during Lactation:Very small amounts of mefloquine are excreted in breastmilk; the amount of drug is not sufficient to harm the infant nor is the quantity sufficient to protect the child from malaria. Breastfeeding infants should receive the recommended dosages of mefloquine.
◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.
There is a possible increase in the risk of arrhythmias if mefloquine is given together with beta blockers, calcium channel blockers, amiodarone, pimozide, digoxin or antidepressants; there is also a possible increase in the risk of convulsions with chloroquine and quinine. Mefloquine concentrations are increased when given with ampicillin, tetracycline and metoclopramide. Caution should be observed with alcohol.
Concomitant administration of mefloquine and other related antimalarial compounds (e.g., quinine, quinidine and chloroquine) may produce electrocardiographic abnormalities and increase the risk of convulsions. If these drugs are to be used in the initial treatment of severe malaria, mefloquine administration should be delayed at least 12 hours after the last dose. Clinically significant QTc prolongation has not been found with mefloquine alone.
Mefloquine is reasonably well absorbed from the gastrointestinal tract but there is marked interindividual variation in the time required to achieve peak plasma concentrations. ... Mefloquine undergoes enterohepatic recycling. It is approximately 98% bound to plasma proteins and is widely distributed throughout the body. The pharmacokinetics of mefloquine may be altered by malaria infection with reduced absorption and accelerated clearance. ... Mefloquine is excreted in small amounts in breast milk. It has a long elimination half-life of around 21 days, which is shortened in malaria to about 14 days, possibly because of interrupted enterohepatic cycling. Mefloquine is metabolized in the liver and excreted mainly in the bile and feces. Its pharmacokinetics show enantioselectivity after administration of the racemic mixture, with higher peak plasma concentrations and area under the curve values, and lower volume of distribution and total clearance of the SR enantiomer than its RS antipode.
The bioavailability of the tablet formulation compared with an oral solution was over 85%. The presence of food significantly enhances the rate and extent of absorption, leading to about a 40% increase in bioavailability. Plasma concentrations peak 6-24 hours (median, about 17 hours) after a single oral dose of mefloquine. Maximum plasma concentrations in ug/L are roughly equivalent to the dose in milligrams (for example, a single 1000 mg dose produces a maximum concentration of about 1000 ug/L). At a dose of 250 mg once weekly, maximum steady state plasma concentrations of 1000-2000 ug/L are reached after 7-10 weeks.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
分布到血液、尿液、脑脊液和组织中；在红细胞中浓缩...
Distributed to blood, urine, CSF, and tissues; concentrated in erythrocytes...
In healthy adults, the apparent volume of distribution is approximately 20 L/kg, indicating extensive tissue distribution. Mefloquine may accumulate in parasitized erythrocytes at an erythrocyte-to-plasma concentration ratio of about 2. Protein binding is about 98%. Mefloquine blood concentrations of 620 ng/mL are considered necessary to achieve 95% prophylactic efficacy.
[EN] CRYSTALLINE FORMS OF (+)- AND (-)-ERYTHRO-MEFLOQUINE HYDROCHLORIDE<br/>[FR] FORMES CRISTALLINES D'HYDROCHLORURE D'ERYTHRO-MEFLOQUINE (+) ET (-)
申请人：ARAKIS LTD
公开号：WO2005058872A1
公开（公告）日：2005-06-30
(+)- or (-)-erythro-Mefloquine hydrochloride can exist in four crystalline forms A, B, C and D, whereby form A is the most stable form. Form A can be directly produced in morphological forms like thick columns, cuboids, cubes and cube-like forms, which can be easily handled during processing and formulation. (+)- or (-)-eroryth-Mefloquine hydrochloride also forms solvates with acetone, methyl ethyl ketone and tetrahydrofuran.
Trapped in Misbelief for Almost 40 Years: Selective Synthesis of the Four Stereoisomers of Mefloquine
作者：Nina Schützenmeister、Michael Müller、Uwe M. Reinscheid、Christian Griesinger、Andrei Leonov
DOI：10.1002/chem.201303403
日期：2013.12.16
an important anti‐malaria drug that is applied as a racemate of the erythro form. However, the (−)‐isomer induces psychosis, while the (+)‐enantiomer does not have this undesired side effect. There are six syntheses of which five lead to the wrong enantiomer without the authors of these synthesesnoting that they had synthesized the wrong compound. At the same time physical chemistry investigations
The present invention relates to certain 2,4-disubstituted quinoline derivatives, to their therapy, as well as to pharmaceutical compositions comprising said compounds. More specifically the invention relates to certain 2,4-disubstituted quinoline derivatives or pharmaceutical compositions comprising said compounds for the treatment of cancers characterized by overactive Ras and/or Rac or signalling pathway.
Enantioselective synthesis method of 4-aminoalcoholquinoline derivatives and the use
申请人：Université de Picardie Jules Verne
公开号：EP2487157A1
公开（公告）日：2012-08-15
Mefloquine derivatives, contrary to chloroquine derivatives have not been widely studied to date. Consequently, mefloquine and its derivatives still remain very attractive synthetic targets. Although mefloquine is usually used clinically as a racemic mixture, some studies have shown that its (+)-enantiomer is more potent than the (-)-enantiomer. Moreover, the (-)-enantiomer is responsible for side effects due to reaction with the central nervous system adenosine receptors, while the (+)-enantiomer does no bind at this binding site. Recently, different libraries of racemate 4-aminoalcoholquinolines showed interesting anti-malarial activities. Herein, the present invention describes an enantiopure synthetic and straightforward route to prepare pure enantiomer 4-aminoalcoholquinoline derivatives through the 4-oxirane key-intermediate. A regioselective SN2 ring opening of this epoxide, by diverse amines, allows to obtain the corresponding (R) or (S) 4-aminoquinolines with good yields and enantiomeric excesses generally superior to 92%. The reported methodology appears suitable for the synthesis of a large number of pure enantiomer 4-aminoalcoholquinoline derivatives.
作者：Dawid J. Kucharski、Rafał Kowalczyk、Przemysław J. Boratyński
DOI：10.1021/acs.joc.1c01316
日期：2021.8.6
11-aminomefloquine with an erythro configuration was obtained by conversion of 11-alcohol into azide and hydrogenation. Alkylation of a secondary amine unit was needed to arrive at diastereomeric threo-11-aminomefloquine and to introduce diversity. Most of the substitution reactions of the hydroxyl group to azido group proceeded with net retention of the configuration and involved actual aziridine or
