安非他酮 | 34911-55-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 安非他酮
• 中文别名: 间氯-α-特丁氨基乙基苯基甲酮；1-(3-氯苯基)-2-[(1,1-二甲基乙基)氨基]-1-丙酮盐酸盐；1-(3-氯苯基)-2-[(1,1-甲基乙基)氨基]-1-丙酮；2-(叔丁基氨基)-1-(3-氯苯基)丙-1-酮
• 英文名称: bupropion
• 英文别名: buproprion；2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one；amfebutamone；bupropion hydrochloride
• CAS: 34911-55-2；144445-76-1；144445-75-0
• 化学式: C₁₃H₁₈ClNO
• mdl: MFCD00865373
• 分子量: 239.745
• InChiKey: SNPPWIUOZRMYNY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  16
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.461
• 拓扑面积：
  29.1
• 氢给体数：
  1
• 氢受体数：
  2

ADMET

代谢

盐酸安非他酮在人体内广泛代谢。有三个活性代谢物：羟基安非他酮，它是通过安非他酮叔丁基团的羟基化形成的，以及氨基酸醇异构体，threohydrobupropion（酸氨基醇异构体）和erythrohydrobupropion（醇氨基醇异构体），它们是通过羰基还原形成的。体外研究发现CYP2B6是形成羟基安非他酮的主要同工酶，而细胞色素P450酶不参与threohydrobupropion的形成。羟基安非他酮已被证明对去甲肾上腺素转运体（NET）的亲和力与安非他酮相同，尽管其浓度比母药高约10倍，但其抗抑郁活性大约只有50%。安非他酮侧链的氧化导致形成meta-氯苯甲酸甘氨酸结合物，然后作为主要尿液代谢物排出。代谢物相对于安非他酮的活性和毒性尚未完全表征。然而，在小鼠的抗抑郁筛选测试中已经证明，羟基安非他酮的效力是安非他酮的一半，而threohydrobupropion和erythrohydrobupropion的效力比安非他酮低5倍。这可能是临床上的重要性，因为代谢物的血浆浓度与安非他酮相当或更高。安非他酮及其代谢物在每天300到450毫克的长期给药后表现出线性动力学。

Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day.

来源:DrugBank

代谢

布普罗品似乎被广泛代谢，可能是在肝脏中。已识别的3种活性代谢物是通过羰基还原和/或羟基化形成的。已识别的基本代谢物包括布普罗品的erythro-和threo-氨基酸醇，以及一个吗啉醇代谢物。氨基酸醇异构体threohydrobupropion和erythrohydrobupropion是通过布普罗品羰基还原形成的，而吗啉醇代谢物，羟基布普罗品，是通过布普罗品叔丁基团的羟基化形成的。在每日剂量为300-450毫克的慢性给药期间，布普罗品的代谢物表现出线性药代动力学。

Bupropion appears to be metabolized extensively, probably in the liver. The 3 active metabolites that have been identified are formed through reduction of the carbonyl group and/or hydroxylation. The basic metabolites identified include the erythro- and threo-amino alcohols of bupropion, and a morpholinol metabolite. The amino-alcohol isomers threohydrobupropion and erythrohydrobupropion are formed by reduction of the carbonyl group of bupropion, and the morpholinol metabolite, hydroxybupropion, is formed by hydroxylation of the tert-butyl group of bupropion. The metabolites of bupropion exhibit linear pharmacokinetics during chronic administration of the drug at dosages of 300-450 mg daily.

来源:Hazardous Substances Data Bank (HSDB)

代谢

所有可用的抗抑郁药除了氟伏沙明和奈法唑酮，要么被细胞色素P450 2D6（CYP2D6）代谢，要么抑制这种同工酶。迄今为止，关于布普品还没有这方面的发表。我们报告了布普品及其代谢物erythrohydrobupropion和threohydrobupropion的血浆水平/剂量比与12名患者的去甲丙米嗪代谢状况无关，其中3名患者是2D6代谢不良者。然而，代谢物羟基布普品的血浆水平/剂量比在2D6代谢不良者中显著较高。在3名在布普品治疗期间接受第二次表型测试的患者中，去甲丙米嗪代谢比没有增加。因此，可以推断布普品既不由CYP2D6代谢也不抑制CYP2D6。然而，CYP2D6抑制后羟基布普品的潜在积累可能会导致毒性并影响布普品的治疗效果。

All available antidepressants with the exception of fluvoxamine and nefazodone either are metabolized by cytochrome P450 2D6 (CYP2D6) and/or inhibit this isozyme. To date, nothing in this regard has been published concerning bupropion. We report that plasma level/dose ratios for bupropion, and its metabolites erythrohydrobupropion and threohydrobupropion, were not associated with debrisoquine metabolic status in 12 patients, three of whom were poor 2D6 metabolizers. The plasma level/dose ratios for the metabolite hydroxybupropion were, however, significantly higher in poor 2D6 metabolizers. In three patients, who received a second phenotyping test during treatment with bupropion, debrisoquine metabolic ratios were not increased. It is thus inferred that bupropion is neither metabolized by nor inhibits CYP2D6. The potential accumulation of hydroxybupropion after CYP2D6 inhibition may, however, contribute to toxicity and impair bupropion's therapeutic effectiveness

来源:Hazardous Substances Data Bank (HSDB)

代谢

盐酸安非他酮是一种新型的单环抗抑郁药。在人身上，它的处置会导致形成三种主要代谢物：吗啉醇代谢物、erythro氨基酸醇和threo氨基酸醇代谢物。在8名健康志愿者和8名年龄（44.5±8.4岁）和体重（77.4±6.7公斤）相匹配的酒精性肝病患者中，单次口服200毫克剂量的安非他酮处置情况进行了监测。后者组别值得关注，因为酒精中毒患者的抑郁发生率高于普通人群，而且肝脏是循环抗抑郁药的主要消除途径。吗啉醇代谢物的平均消除半衰期在酒精性肝病患者中显著延长（32.2±13.5小时对21.1±4.9小时（p<0.05），而安非他酮（17.3±8.6小时对16.5±10.4小时，分别为健康受试者和酒精性肝病患者）、erythro氨基酸醇（26.1±13.3小时对29.8±6.9小时，分别为健康受试者和酒精性肝病患者）和threo氨基酸醇（25.5±8.6小时对23.4±10.7小时，分别为健康受试者和酒精性肝病患者）的差异最小。安非他酮及其代谢物的平均血药浓度-时间曲线下面积在酒精性肝病患者中增加；然而，由于这些受试者安非他酮药代动力学的变异性增加，这些小群体之间的明显差异并未出现。作为一种治疗慢性酒瘾患者抑郁的治疗药物，这些患者可能会将酒精与他们的抗抑郁治疗相结合，安非他酮没有镇静作用可能是一个优势。

Bupropion hydrochloride is a new monocyclic antidepressant. In humans, its disposition results in the formation of three major metabolites: the morpholinol metabolite, the erythroamino alcohol, and the threoamino alcohol metabolite. Bupropion's disposition was monitored following a single oral 200 mg dose in eight healthy volunteers and eight age- (44.5 +/- 8.4 years) and weight- (77.4 +/- 6.7 kg) matched volunteers with alcoholic liver disease. This latter group is of interest because the incidence of depression is more frequent in alcoholics than in the general population, and the liver is the major route of elimination for cyclic antidepressants. The mean elimination half-life of the morpholinol metabolite was significantly prolonged in subjects with alcoholic liver disease (32.2 +/- 13.5 vs. 21.1 +/- 4.9 hours (p less than 0.05), while the differences in bupropion (17.3 +/- 8.6 hours vs. 16.5 +/- 10.4 hours for healthy subjects and subjects with alcoholic liver disease, respectively), erythroamino alcohol (26.1 +/- 13.3 hours vs. 29.8 +/- 6.9 hours for healthy subjects and subjects with alcoholic liver disease, respectively), and threoamino alcohol (25.5 +/- 8.6 hours vs. 23.4 +/- 10.7 hours for healthy subjects and subjects with alcoholic liver disease, respectively) were minimal. Mean area under the plasma concentration time curves for bupropion and metabolites were increased in subjects with alcoholic liver disease; however, clear differences between means of these small groups did not emerge, probably due to the increased variability of bupropion pharmacokinetics in these subjects. As a therapeutic agent for the treatment of depression in chronic alcoholics who may consume alcohol in combination with their antidepressant therapy, the lack of sedation with bupropion could be advantageous.

来源:Hazardous Substances Data Bank (HSDB)

代谢

我们研究了盐酸安非他酮的稳态药代动力学，安非他酮是一种单环氨基酮类抗抑郁药，在抑郁症患者中进行了研究。在稳态下，代谢物羟基安非他酮（HB）、赤藓糖安非他酮和苏阿糖安非他酮在血浆和脑脊液中的浓度超过了母化合物。每种代谢物的血浆浓度与脑脊液浓度相关。较高的血浆代谢物浓度与较差的临床结果相关。这种关系在HB上最为显著；所有五个无反应者的血浆HB水平均大于1250 ng/mL，而七个反应者的血浆HB水平均低于1200 ng/mL。血浆HB水平与治疗后血浆香草酸水平相关。高水平的安非他酮代谢物可能与由于涉及多巴胺系统的毒性效应而导致的较差临床结果有关。另外，安非他酮代谢物可能存在非线性剂量反应关系。未来的研究应该探讨通过测量血浆代谢物来提高安非他酮治疗有效性的临床实用性。

We studied the steady-state pharmacokinetics of bupropion hydrochloride, a unicyclic aminoketone antidepressant, in depressed patients. The metabolites hydroxybupropion (HB), threohydrobupropion, and erythrohydrobupropion predominated over the parent compound in plasma and cerebrospinal fluid at steady state. Plasma concentrations of each metabolite correlated with cerebrospinal fluid concentrations. Higher plasma metabolite concentrations were associated with poor clinical outcome. This relationship was most striking with HB; plasma HB levels were greater than 1250 ng/mL in all five nonresponders and less than 1200 ng/mL in all seven responders. Plasma HB levels correlated with postreatment plasma homovanillic acid levels. High levels of bupropion metabolites may be associated with poor clinical outcome due to toxic effects involving dopaminergic systems. Alternatively, a curvilinear dose-response relationship may exist for bupropion metabolites. Future studies should explore the clinical utility of plasma metabolite measurements in enhancing the efficacy of treatment with bupropion.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和用途：安非他酮是一种淡黄色油性物质，以缓释口服片的形式制备。安非他酮是一种多巴胺摄取抑制剂，用作第二代抗抑郁药。人类暴露和毒性：安非他酮是一种常作为戒烟辅助药物的抗抑郁药。它对多巴胺和去甲肾上腺素有作用，并且可能降低癫痫阈值，尤其是在过量时。文献中已有几例通过鼻腔吸人滥用安非他酮的报告。安非他酮可能最严重的副作用之一是降低癫痫阈值。然而，尽管这种效应的潜在严重性，癫痫仍然是安非他酮治疗中相对不常见的不良反应。据报道，患者过量服用了30克或更多的安非他酮盐酸。过量服用严重效果包括约三分之一的病人出现癫痫，幻觉，意识丧失，窦性心动过速，以及ECG改变，如传导障碍或心律失常。过度嗜睡、昏昏欲睡、颤抖、紧张不安、混乱、头晕、感觉异常、视觉幻觉、视力模糊、恶心和呕吐也发生了。安非他酮过量（主要是作为多药过量的部分）据报道已导致发热、肌肉僵直、横纹肌溶解症、低血压、昏迷和呼吸衰竭。大多数人在单独过量服用安非他酮后没有后遗症地恢复。然而，单独大量过量服用安非他酮极为罕见地会导致在多次无法控制的癫痫、心动过缓、心力衰竭和心脏骤停之前死亡。心脏毒性似乎主要由安非他酮而不是其活性代谢物羟基安非他酮引起。年幼儿童无意中摄入安非他酮一般导致有限的毒性。在两例归因于安非他酮的死亡中，两种情况的剂量估计都不到10克。动物研究：在给大鼠或小鼠终身致癌性研究中，分别每天接受100-300或150毫克/公斤的安非他酮盐酸剂量，在大鼠中观察到肝脏结节增殖性病变的增加，但在小鼠中没有观察到。这些病变与肝脏肿瘤发展的关系尚不清楚。在大鼠或小鼠中未观察到肝脏和其他器官恶性肿瘤的增加。在一项使用口服安非他酮的大鼠研究中，每天剂量高达300毫克/公斤，没有发现影响生育力的证据。在大鼠配种前和整个怀孕和哺乳期间每天口服安非他酮高达300毫克/公斤，对后代发育没有明显的负面影响。在在大鼠和兔子的发育研究中，没有发现明确的致畸活性证据，但在兔子的胎儿畸形和骨骼变异的发病率略有增加。安非他酮在大鼠和小鼠中诱导行为改变。安非他酮在沙门氏菌微生物突变（Ames）测试系统中表现出致突变活性；在5个菌株中的2个，突变率是对照组的2-3倍。在一项使用大鼠骨髓的3个体内细胞遗传学研究中，观察到染色体的异常增加。

IDENTIFICATION AND USE: Bupropion is pale yellow oil formulated in extended release oral tablets. Bupropion is a dopamine uptake inhibitor, which is used as a second generation antidepressive agent. HUMAN EXPOSURE AND TOXICITY: Bupropion is an antidepressant commonly prescribed as a smoking cessation aid. It has effects on dopamine and norepinephrine, and can lower seizure threshold, particularly in overdose. Several cases of recreational use of bupropion via nasal insufflation have been reported in the literature. One of the potentially most serious adverse effects of bupropion is reduction in the seizure threshold. However, despite the potential seriousness of this effect, seizures remain a relatively uncommon adverse effect of bupropion therapy. Patients reportedly have overdosed with 30 g or more of bupropion hydrochloride. Serious effects of overdosage have included seizures in about one-third of such patients, hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conduction disturbances or arrhythmias. Lethargy, grogginess, tremors, jitteriness, confusion, lightheadedness, paresthesias, visual hallucinations, blurred vision, nausea, and vomiting also have occurred. Overdosage of bupropion (mainly as part of multiple drug overdoses) reportedly has resulted in fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. Recovery without sequelae has been reported in most individuals following an overdose of bupropion alone. However, massive overdosage of bupropion alone has been reported rarely to result in death preceded by multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest. Cardiotoxicity appears to be caused primarily by bupropion rather than its active metabolite hydroxybupropion. Unintentional ingestion of bupropion in young children has generally resulted in limited toxicity. In two deaths attributed to bupropion, the doses in both cases were estimated to be less than 10 g. ANIMAL STUDIES: In lifetime carcinogenicity studies of rats or mice receiving bupropion hydrochloride dosages of 100-300 or 150 mg/kg daily respectively, an increase in nodular proliferative lesions of the liver was observed in rats but not in mice. The relationship of these lesions to the development of neoplasms of the liver is unclear. An increase in malignant tumors of the liver and other organs was not observed in either rats or mice. A fertility study in rats using oral bupropion hydrochloride dosages of up to 300 mg/kg daily did not reveal evidence of impaired fertility. In rats receiving oral dosages of bupropion of up to 300 mg/kg daily prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development. In developmental studies performed in rats and rabbits, no clear evidence of teratogenic activity was found in either species, but slightly increased incidences of fetal malformations and skeletal variations were observed in rabbits. Bupropion induced behavioral changes in rats and mice. Bupropion exhibited mutagenic activity in the Salmonella microbial mutagen (Ames) test system; the mutation rate was 2-3 times control in 2 of 5 strains. An increase in chromosomal aberrations was observed in one of 3 in vivo cytogenetic studies conducted with the bone marrow of rats.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

盐酸安非他酮是选择性去甲肾上腺素再摄取抑制剂，主要用于辅助戒烟。通过选择性抑制神经元对多巴胺、去甲肾上腺素和5-羟色胺的再摄取，增强这些神经递质的功能，从而减轻戒烟时的戒断症状和烟瘾。

Bupropion selectively inhibits the neuronal reuptake of dopamine, norepinephrine, and serotonin; actions on dopaminergic systems are more significant than imipramine or amitriptyline whereas the blockade of norepinephrine and serotonin reuptake at the neuronal membrane is weaker for bupropion than for tricyclic antidepressants. The increase in norepinephrine may attenuate nicotine withdrawal symptoms and the increase in dopamine at neuronal sites may reduce nicotine cravings and the urge to smoke. Bupropion exhibits moderate anticholinergic effects.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

肝脏测试异常在接受安非他酮治疗的患者中报告发生率不到1%，而且升高的幅度通常较小，通常不需要调整剂量或停药。在接受安非他酮治疗的患者中，有罕见的情况出现急性、临床上明显的肝脏损伤，表现为肝酶显著升高，伴有或不伴有黄疸（案例1）。损伤的发生通常在1到3个月内，血清酶升高的模式各不相同，从肝细胞损伤到胆汁淤积。一部分案例中发现了自身免疫（自身抗体），但滴度较低。免疫过敏特征（皮疹、发热、嗜酸性粒细胞增多）不常见。这种损伤通常是自限性的，但已有致命案例的报告。

Liver test abnormalities have been reported to occur in less than 1% of patients on bupropion, and 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 bupropion (Case 1). The onset of injury is usually within 1 to 3 months and the pattern of serum enzyme elevations has been variable, from hepatocellular to cholestatic. Autoimmune (autoantibodies) are found in a proportion of cases, but in low titer. Immunoallergic features (rash, fever, eosinophilia) are uncommon. The injury is generally self-limited, but fatal cases have been reported.

来源:LiverTox

毒理性

• 药物性肝损伤

药物：安非他酮

Compound:bupropion

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：低药物性肝损伤关注

DILI Annotation:Less-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

目前，安非他酮有三种不同的但生物等效的制剂形式：立即释放（IR）、持续释放（SR）和延长释放（XL）。 **立即释放制剂** 在人体内，安非他酮盐酸片口服给药后，通常在2小时内达到血浆安非他酮浓度的峰值。IR制剂的作用持续时间短，因此通常一天三次给药。 **持续释放制剂** 在人体内，安非他酮盐酸持续释放片（SR）口服给药后，安非他酮的血浆峰浓度（Cmax）通常在3小时内达到。SR制剂提供12小时的药物延长释放，因此通常一天两次给药。 **延长释放制剂** 对健康志愿者单次口服安非他酮盐酸延长释放片（XL）后，安非他酮达到血浆峰浓度的时间中位数大约是5小时。食物的存在并不影响安非他酮的峰浓度或曲线下面积。XL制剂提供24小时的药物延长释放，因此通常一天一次给药。 在一项比较安非他酮盐酸持续释放片（SR）150毫克一天两次与安非他酮立即释放制剂100毫克一天三次的长期给药的试验中，SR给药后安非他酮的稳态Cmax大约是立即释放制剂的85%。两种制剂的安非他酮暴露（AUC）是等效的。对于所有三种主要活性代谢物（即羟基安非他酮、赤藓糖安非他酮和苏力糖安非他酮）的Cmax和AUC也展示了生物等效性。因此，在稳态下，一天两次给药的安非他酮盐酸持续释放片（SR）和一天三次给药的安非他酮立即释放制剂对于安非他酮及其三种重要的代谢物基本上是生物等效的。 此外，在一项比较14天给药安非他酮盐酸延长释放片（XL）300毫克一天一次与安非他酮立即释放制剂100毫克一天三次的研究中，对于安非他酮及其三种代谢物（羟基安非他酮、赤藓糖安非他酮和苏力糖安非他酮）的峰浓度和曲线下面积展示了等效性。同样，在一项比较14天给药安非他酮盐酸延长释放片（XL）300毫克一天一次与安非他酮持续释放制剂150毫克一天两次的研究中，对于安非他酮及其三种代谢物的峰浓度和曲线下面积也展示了等效性。 安非他酮盐酸持续释放片（SR）可以在有食物或没有食物的情况下服用。在三项试验中，当安非他酮盐酸持续释放片（SR）与食物一起给予健康志愿者时，安非他酮的Cmax和AUC分别增加了11%至35%和16%至19%。食物的影响被认为在临床上不显著。 在人体内单次给药安非他酮盐酸持续释放片（SR）后，安非他酮的代谢物羟基安非他酮的Cmax大约在给药后6小时发生，并且在其稳态时大约是母药峰水平的10倍。羟基安非他酮的消除半衰期大约是20（±5）小时，其在稳态时的AUC是安非他酮的约17倍。赤藓糖安非他酮和苏力糖安非他酮代谢物达到峰浓度的时间与羟基安非他酮代谢物相似。然而，它们的消除半衰期更长，分别为33（±10）小时和37（±13）小时，稳态AUC分别是安非他酮的1.5倍和7倍。

Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). **Immediate Release Formulation** In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. **Sustained Release Formulation** In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. **Extended Release Formulation** Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively.

来源:DrugBank

吸收、分配和排泄

• 消除途径

Bupropion在人体内被广泛代谢。Bupropion侧链的氧化导致形成甲氯苯甲酸甘氨酸结合物，然后作为主要的尿液代谢物被排出。在人体口服200毫克14C-bupropion后，放射性剂量的87%和10%分别在尿液和粪便中回收。然而，口服剂量的bupropion以原形排出的部分仅为0.5%，这一发现与bupropion的广泛代谢一致。

Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion.

来源:DrugBank

吸收、分配和排泄

常规或缓释膜衣片（Wellbutrin SR，Zyban）口服给药后，健康个体的峰血浆安非他酮浓度通常在2到3小时内出现。单次口服100-250毫克安非他酮剂量后以及每日长期服用最高450毫克的剂量下，血浆安非他酮浓度与剂量成正比。安非他酮的稳态血浆浓度在8天内达到。在以100毫克每日三次或150毫克每日两次的剂量长期服用安非他酮盐酸普通或缓释膜衣片的情况下，稳态时缓释片的峰血浆浓度约为普通片的85%。安非他酮在不同制剂之间的血浆浓度-时间曲线下面积（AUC）等效性得到了证实，这表明在稳态时，普通片和缓释片基本上生物等效。在每日服用300-450毫克安非他酮盐酸的剂量下，该药物表现出线性药代动力学。

Peak plasma bupropion concentrations usually occur within 2 or 3 hours after oral administration of the conventional or extended-release, film-coated tablets (Wellbutrin SR, Zyban), respectively, to healthy individuals. Plasma bupropion concentrations following administration of single oral doses of 100-250 mg and with chronic administration of up to 450 mg daily are proportional to dose. Steady-state plasma concentrations of bupropion are achieved within 8 days. During chronic administration of bupropion hydrochloride as conventional or extended-release, film-coated tablets at a dosage of 100 mg 3 times daily or 150 mg twice daily, respectively, peak plasma concentrations of the drug at steady state with extended-release tablets were about 85% of measurements for the conventional tablets. Equivalence in area under the plasma concentration-time curve (AUC) of bupropion was shown for the formulations, which demonstrated that at steady state the conventional and extended-release tablets are essentially bioequivalent. The drug exhibits linear pharmacokinetics during chronic administration of bupropion hydrochloride dosages of 300-450 mg daily.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

盐酸安非他酮口服给药后似乎能很好地从胃肠道吸收。由于没有可用于静脉给药的制剂，因此尚未阐明人类安非他酮的口服生物利用度。然而，口服剂量中不变地达到系统循环的相对比例似乎很小。在动物中，安非他酮的口服生物利用度从5-20%不等。食物似乎不会显著影响服用安非他酮缓释片后达到的峰值血浆浓度或血浆浓度-时间曲线下的面积；据报道，这些指标在食物的影响下分别增加了11%或17%。

Bupropion hydrochloride appears to be well absorbed from the GI tract following oral administration. The oral bioavailability of bupropion in humans has not been elucidated because a preparation for IV administration is not available. However, the relative proportion of an oral dose reaching systemic circulation unchanged appears likely to be small. In animals, the oral bioavailability of bupropion varies from 5-20%. Food does not appear to affect substantially the peak plasma concentration or area under the plasma concentration-time curve of bupropion achieved with extended-release tablets of the drug; these measures reportedly were increased with food by 11 or 17%, respectively.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

大约87%和10%的口服给药、放射性标记的安非他酮剂量分别在尿液和粪便中排出，未改变的药物占排泄剂量的0.5%。

Approximately 87 and 10% of an orally administered, radiolabeled dose of bupropion are excreted in urine and feces, respectively. Unchanged drug comprised 0.5% of the dose excreted.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  安非他酮 在 2-(二环己基膦)3,6-二甲氧基-2′,4′,6′-三异丙基-1,1′-联苯 、 硼酸 、 palladium diacetate 、 caesium carbonate 作用下， 以 N-甲基吡咯烷酮 为溶剂， 反应 14.0h， 以68%的产率得到1-(3-hydroxyphenyl)-2-(tert-butylamino)propan-1-one
  参考文献：
  名称：

  硼酸与硼酸的钯催化羟基化

  摘要：

  硼酸B（OH）3被证明是在温和条件下用Pd催化剂将卤代（杂）芳基卤化物转化为相应酚的有效氢氧化物试剂。以良好至优异的产率获得了各种苯酚产物。这种转变可耐受各种官能团和分子，包括对碱敏感的取代基和复杂的药学（杂）芳基卤化物分子。

  DOI：

  10.1021/acs.orglett.0c03069
• 作为产物：
  描述：

  (+/-)-1-[(tert-butyldimethylsilyl)oxy]-1-(3-chlorophenyl)propan-2-one 在 2,6-二甲基吡啶 、 sodium tetrahydroborate 、 三氟甲磺酸酐 、 四丁基氟化铵 、 2-碘酰基苯甲酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 二甲基亚砜 为溶剂， 反应 46.67h， 生成 安非他酮
  参考文献：
  名称：

  Hyphenating the curtius rearrangement with Morita-Baylis-Hillman adducts: synthesis of biologically active acyloins and vicinal aminoalcohols

  摘要：

  DOI：

  10.1590/s0103-50532011000800022
• 作为试剂：
  描述：

  2-溴-3'-氯苯丙酮 、 叔丁胺 在 叔丁胺 、 甲苯 、 水 、 magnesium sulfate 、 安非他酮 作用下， 反应 5.5h， 生成 安非他酮
  参考文献：
  名称：

  Process for preparing bupropion hydrochloride

  摘要：

  该发明描述了一种合成盐酸布洛芬的方法。m-氯代苯丙酮直接与溴反应，然后用叔丁胺进行氨基化反应，最后与HCl反应得到粗品盐酸布洛芬。通过重结晶后获得纯品。该方法成本低廉，产量高，副产物少且环保，适用于商业生产。

  公开号：

  US20090012328A1

文献信息

• [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.

  MCHR1拮抗剂具有以下化学式（I）：A1和A2独立地为C或N；E为C或N；Q1、Q2和Q3独立地为C或N，但至少其中一个为N，但不超过一个为N；D1为键，-CR8R9 X-，-XCR8R9-，-CHR8CHR9-，-CR10=CR10'-，-C≡C-，或1,2-环丙基；X为O、S或NR11；R1、R2和R3独立地从氢、卤素、低烷基、低环烷基、-CF3、-OCF3、-OR12和-SR12组成的群体中选择；G为O、S或-NR15；D2为低烷基、低环烷基、低烷基环烷基、低环烷基烷基、低环烷氧基烷基或低烷基环烷氧基，或当G为NR15时，G和D2一起可以选择形成氮杂环丙烷、吡咯烷或哌啶环；Z1和Z2独立地为氢、低烷基、低环烷基、低烷氧基、低环烷氧基、卤素、-CF3、-OCONR14R14'、-CN、-CONR14R14'、-SOR12、-SO2R12、-NR14COR14'、-NR14CO2R14'、-CO2R12、NR14SO2R12或COR12；R5、R6和R7独立地从氢、低烷基、低环烷基、-CF3、-SR12、低烷氧基、低环烷氧基、-CN、-CONR14R14'、SOR12、SO2R12、NR14COR14'、NR14CO2R12、CO2R12、NR14SO2R12和-COR12组成的群体中选择；R8、R9、R10、R10'、R11独立地为氢或低烷基；R12为低烷基或低环烷基；R14和R14'独立地为H、低烷基、低环烷基或R14和R14'与其连接的N一起形成具有4至7个原子的环；R15独立地从氢和低烷基组成的群体中选择。这些化合物对于治疗MCHR1介导的疾病，如肥胖症、糖尿病、炎症性肠病、抑郁症和焦虑症非常有用。
• [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.

  本申请涉及式(I)、(Ia)或(Ib)的化合物及其药物组合物/制剂。本申请进一步涉及治疗或预防与Αβ相关的病理学，如唐氏综合症，β-淀粉样蛋白血管病，如但不限于脑淀粉样蛋白血管病或遗传性脑出血，与认知损害相关的疾病，如但不限于MCI（“轻度认知损害”），阿尔茨海默病，记忆丧失，与阿尔茨海默病相关的注意力缺陷症状，与疾病如阿尔茨海默病或痴呆症相关的神经退行性疾病，包括混合性血管性和退行性起源的痴呆，早老性痴呆，老年性痴呆和与帕金森病相关的痴呆的方法。
• [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.

  本发明涉及甲基噁唑化合物，其为促进睡眠的受体拮抗剂。本发明还涉及所述化合物在潜在治疗或预防涉及促进睡眠的神经和精神疾病和疾病中的用途。本发明还涉及包含这些化合物的组合物。本发明还涉及这些组合物在潜在预防或治疗涉及促进睡眠的疾病中的用途。
• HETEROBICYCLIC COMPOUNDS
  申请人：Amgen Inc.

  公开号：US20130225552A1

  公开（公告）日：2013-08-29

  Heterobicyclic compounds of Formula (I): or a pharmaceutically-acceptable salt, tautomer, or stereoisomer thereof, as defined in the specification, and compositions containing them, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, Huntington's Disease, and the like.

  Formula (I)的杂环化合物： 或其药用可接受的盐、互变异构体或立体异构体，如规范中所定义，并含有它们的组合物，以及制备这种化合物的方法。本文还提供了通过抑制PDE10来治疗由此可治疗的疾病或疾病的方法，如肥胖症、非胰岛素依赖型糖尿病、精神分裂症、躁郁症、强迫症、亨廷顿病等。
• [EN] NAPHTHALENE CARBOXAMIDE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS<br/>[FR] COMPOSÉS DE NAPHTHALÈNE CARBOXAMIDE, MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR M1
  申请人：MERCK SHARP & DOHME

  公开号：WO2011149801A1

  公开（公告）日：2011-12-01

  The present invention is directed to naphthalene carboxamide compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimers disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.

  本发明涉及式(I)的萘甲酰胺化合物，它们是M1受体阳性变构调节剂，可用于治疗M1受体参与的疾病，如阿尔茨海默病、精神分裂症、疼痛或睡眠障碍。该发明还涉及包含这些化合物的药物组合物，以及在治疗由M1受体介导的疾病中使用这些化合物和组合物。