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2-[(4R,5S,6S,7R,9R,10R,16R)-6-[(2S,3R,4S,6R)-5-[(2S,4R,5S)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-10-[(2R,5S,6R)-5-(dimethylamino)-6-methyloxan-2-yl]oxy-4-hydroxy-5-methoxy-9,16-dimethyl-2-oxo-1-oxacyclohexadeca-11,13-dien-7-yl]acetaldehyde

中文名称
——
中文别名
——
英文名称
2-[(4R,5S,6S,7R,9R,10R,16R)-6-[(2S,3R,4S,6R)-5-[(2S,4R,5S)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-10-[(2R,5S,6R)-5-(dimethylamino)-6-methyloxan-2-yl]oxy-4-hydroxy-5-methoxy-9,16-dimethyl-2-oxo-1-oxacyclohexadeca-11,13-dien-7-yl]acetaldehyde
英文别名
——
2-[(4R,5S,6S,7R,9R,10R,16R)-6-[(2S,3R,4S,6R)-5-[(2S,4R,5S)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-10-[(2R,5S,6R)-5-(dimethylamino)-6-methyloxan-2-yl]oxy-4-hydroxy-5-methoxy-9,16-dimethyl-2-oxo-1-oxacyclohexadeca-11,13-dien-7-yl]acetaldehyde化学式
CAS
——
化学式
C43H74N2O14
mdl
——
分子量
843.1
InChiKey
ACTOXUHEUCPTEW-VRCNPYAISA-N
BEILSTEIN
——
EINECS
——
  • 物化性质
  • 计算性质
  • ADMET
  • 安全信息
  • SDS
  • 制备方法与用途
  • 上下游信息
  • 反应信息
  • 文献信息
  • 表征谱图
  • 同类化合物
  • 相关功能分类
  • 相关结构分类

计算性质

  • 辛醇/水分配系数(LogP):
    2.1
  • 重原子数:
    59
  • 可旋转键数:
    11
  • 环数:
    4.0
  • sp3杂化的碳原子比例:
    0.86
  • 拓扑面积:
    195
  • 氢给体数:
    4
  • 氢受体数:
    16

ADMET

代谢
在牛体内,形成了新斯皮拉霉素这种代谢物,它是脱糖基衍生物。在给药后14-28天,肌肉和肾脏中新斯皮拉霉素的浓度略高于 spiramycin;在肌肉中,新斯皮拉霉素和 spiramycin的水平大约相等。
In cattle, the metabolite neospiramycin, the demycarosyl derivative, is formed. Concentrations of neospiramycin in muscle and kidney were marginally higher than those of spiramycin 14-28 days after dosing; in muscle, levels of neospiramycin and spiramycin were approximately equal.
来源:Hazardous Substances Data Bank (HSDB)
代谢
spiramycin在肝脏中代谢为活性代谢物;大量通过胆汁排出,约10%通过尿液排出。
Spiramycin is metabolized in the liver to active metabolites; substantial amounts are excreted in the bile and about 10% in the urine.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 毒性总结
识别和使用:螺旋霉素是一种大环内酯类抗生素,用于治疗和控制动物中多种细菌和支原体感染。它以螺旋霉素磷酸盐的形式用于动物饲料,并作为更易溶的螺旋霉素酯形式通过其他途径给药。它还被用于治疗原虫感染,如隐孢子虫病和弓形虫病。人类暴露和毒性:据报道,螺旋霉素在职业环境中会引起接触性皮炎。一名在饲料厂工作的男子由于空气中的螺旋霉素而患上了过敏性接触性皮炎。患者在工作期间裸露区域出现反复的湿疹病变。螺旋霉素还据报道会引起过敏反应。一名34岁的女性在制药厂处理螺旋霉素粉末时出现了鼻炎和刺激性咳嗽。接触药物后几小时内出现症状,并在离开工作场所后持续数小时。一名35岁的非过敏性维护工程师在制药行业工作一年后出现了打喷嚏、咳嗽和呼吸困难的发作。在医院进行的逐渐增加螺旋霉素剂量的吸入挑战测试重现了他的症状,并导致了迟发型哮喘反应的发生。此外,还报告了两例制药厂工人因螺旋霉素引起的支气管哮喘。受试者在接触螺旋霉素粉末时在工作时出现咳嗽、呼吸困难和哮喘症状。离开工作3或4天后症状消失。动物研究:每组2只雄性和2只雌性猴子(Macaca fascicularis)每天静脉注射0、240,000、360,000和540,000 IU/kg bw的螺旋霉素酯,持续5天。所有剂量组在注射期间都出现过度流涎。在几只高剂量猴子和一只低剂量猴子中出现肌肉张力减退和恶心性痉挛。体重没有异常,但所有处理动物的食物消耗量都减少了。在高剂量动物中注意到血红蛋白、红细胞数量和血细胞比容略有下降。在大鼠进行的短期饮食研究中,给予相当于最高3900 mg/kg bw的剂量,持续13周,注意到的唯一主要效果是一些中剂量和高剂量动物的中性粒细胞计数减少,以及盲肠扩张。在另一项大鼠饮食研究中,动物被给予相当于最高720 mg/kg bw/day的剂量,持续一年。注意到的唯一显著效果是高剂量雌性动物的体重减轻,以及高剂量水平下两性动物的相对肝、肾和肾上腺重量增加。在所有剂量水平下都发生了肝糖原耗竭,但对照组没有。在给予杂种犬500 mg/kg bw/day,持续最多56天的研究中,观察到精子生成减少和睾丸萎缩。还看到了肾脏损伤。当比格犬口服螺旋霉素,剂量相当于最高150 mg/kg bw/day,持续两年时,没有观察到睾丸损伤,尽管其他器官发生了退行性变化。在针对小鼠的致畸性研究中,妊娠第5-15天口服螺旋霉素剂量高达400 mg/kg bw对妊娠结果没有影响。大鼠妊娠第6-15天和兔妊娠第6-19天静脉注射高达84 mg/kg bw/day的剂量对发育没有影响,但在兔口服200和400 mg/kg bw/day的剂量时,母兔产生了盲肠扩张。在研究中,20只妊娠大鼠在妊娠第6-15天静脉注射0、90,000、180,000和270,000 IU/kg bw/day的螺旋霉素酯。最高剂量产生了短暂的(5分钟)共济失调和震颤。中间剂量时胎儿体重略有但显著下降,但所有值都在历史对照范围内。在这项研究中没有注意到任何胎儿异常的增加。在一项研究中,雄性大鼠以30 mg/kg bw/day的剂量给药8天,途径未指定,注意到了精原细胞的有丝分裂和减数分裂异常。在体外哺乳动物细胞正向突变试验、体外细胞遗传学分析和小鼠微核试验中,螺旋霉素酯和螺旋霉素磷酸盐均得到了阴性结果。
IDENTIFICATION AND USE: Spiramycin is a macrolide antibiotic used for the treatment and control of a number of bacterial and mycoplasmal infections in animals. It is available as a spiramycin embonate for use in animal feed, and as the adipate, a more soluble form, for administration by other routes. It has also been used in the protozoal infections cryptosporidiosis and toxoplasmosis. HUMAN EXPOSURE AND TOXICITY: Spiramycin is reported to cause contact dermatitis in occupational settings. A man who worked in a feed factory developed allergic contact dermatitis due to airborne spiramycin. The patient suffered recurrent outbreaks of eczematous lesions on uncovered areas during working periods. Spiramycin is also reported to cause hypersensitivity reactions. Rhinoconjunctivitis and spasmodic cough are reported in a 34 year-old female handling spiramycin powder in a pharmaceutical factory. The symptoms appeared within the first few hours of coming into contact with the drug and continued for several hours after leaving her place of work. One year after starting work in the pharmaceutical industry a 35-year-old non-atopic maintenance engineer developed attacks of sneezing, coughing and breathlessness. Inhalation challenge tests carried out in the hospital with gradually increasing quantities of spiramycin reproduced his symptoms and led to the development of late asthmatic reactions. Additionally, two cases of bronchial asthma due to spiramycin in workers of a pharmaceutical factory were reported. The subjects complained of cough, breathlessness and symptoms of asthma at work when coming into contact with spiramycin's powder. The symptoms cleared when away from work for more than 3 or 4 days. ANIMAL STUDIES: Groups of 2 male and 2 female monkeys (Macaca fascicularis) were given daily intravenous injections of 0, 240,000, 360,000, and 540,000 iu/kg bw/day spiramycin adipate for 5 days. Hypersalivation occurred during injection in all dose groups. Muscle hypotonia and nauseous spasticity occurred in several high dose monkeys and in one given the low dose. No abnormalities of body weights occurred but food consumption was reduced in all treated animals. A slight decrease in hemoglobin, red cell numbers and hematocrit was noted in high dose animals. In a short-term dietary study in which rats were given the equivalent of up to 3900 mg/kg bw for 13 weeks, the only major effects noted were a reduction in neutrophil counts in some mid- and high-dose animals, and the dilatation of the caecum. In another dietary study in the rat, animals were given up to the equivalent of 720 mg/kg bw/day for one year. The only notable effects were reductions in the body weights of females receiving the high doses, and increases in relative liver, kidney, and adrenal weights at high dose levels in animals of both sexes. Hepatic glycogen depletion occurred at all dose levels but not in controls. In mongrel dogs given 500 mg/kg bw/day for up to 56 days, reductions in spermatogenesis and testicular atrophy occurred. Kidney damage was also seen. When beagles were given orally spiramycin at up to the equivalent of 150 mg/kg bw/day for two years, testicular damage was not seen although degenerative changes occurred in other organs. In teratogenicity studies in mice, oral doses of spiramycin of up to 400 mg/kg bw given over days 5-15 of gestation had no effects on the outcome of pregnancy. intravenous doses of up to 84 mg/kg bw/day given on days 6-15 of gestation to rats and day 6-19 to rabbits had no effect on developmental, but oral dose of 200 and 400 mg/kg bw/day in rabbit produced caecal enlargement in mothers. Groups of 20 pregnant rats were treated intravenously on days 6-15 of gestation with doses of 0, 90 000, 180 000, and 270 000 iu/kg bw/day with spiramycin adipate. The highest dose given produced brief (5 minutes) ataxia and tremors immediately after dosing. A slight but significant reduction in fetal weight occurred at the intermediate dose but all values were within historical control ranges. There were no increased incidences of any fetal anomaly noted in this study. In a study where male rats were given doses of 30 mg/kg bw/day for 8 days by an unspecified route, mitotic and meiotic abnormalities in spermatogonia were noted. Negative result were obtained with spiramycin adipate and embonate in a forward-mutation test in mammalian cells in vitro, in an in vitro cytogenic assay, and in the mouse micronucleus test.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 相互作用
大环内酯类抗生素包括天然成员、前药和半合成衍生物。这些药物适用于多种感染,并且常常与其他药物疗法联合使用,因此存在潜在的药代动力学相互作用。大环内酯类可以通过在肝脏形成复合物并使微粒体药物氧化酶失活来抑制药物代谢,同时通过其抗生素效果干扰肠内微生物群。在过去的20年中,有多份报告指出大环内酯类是临床严重药物相互作用的潜在来源。然而,不同的大环内酯类在这方面存在差异,并非所有的大环内酯类都会引起药物相互作用。随着许多半合成大环内酯类抗生素的近期出现,现在可以明确它们在引起药物相互作用方面可以分为三个不同的组别。第一组(例如三乙酰螺旋霉素、红霉素)是那些容易形成亚硝基烷烃,从而导致无活性细胞色素P450-代谢物复合物形成的药物。第二组(例如交沙霉素、氟红霉素、罗红霉素、克拉霉素、米卡霉素和米地霉素)形成复合物的程度较小,很少产生药物相互作用。最后一组(例如螺旋霉素、罗吉霉素、地红霉素和阿奇霉素)不会使细胞色素P450失活,也无法改变其他化合物的药代动力学。似乎有两个结构因素对于大环内酯类抗生素导致细胞色素P450的诱导以及体内或体外形成抑制性的细胞色素P450-铁-亚硝基烷代谢物复合物至关重要:大环内酯分子中存在一个非阻碍性的、易于接近的N-二甲氨基团以及药物的疏水性特征。三乙酰螺旋霉素在微粒体肝酶抑制剂中排名第一,会导致甲基强的松龙、茶碱、卡马西平、非那宗(安替比林)和三唑仑的代谢显著减少。三乙酰螺旋霉素可能会导致服用麦角生物碱的患者出现麦角病,以及那些服用口服避孕药的患者出现胆汁淤积性黄疸。红霉素及其不同的前药似乎是对药物代谢的较不强力抑制剂。然而,案例报告和控制研究已经显示红霉素可能会与茶碱、卡马西平、甲基强的松龙、华法林、环孢素、三唑仑、咪达唑仑、阿芬太尼、双异丙吡胺和溴隐亭发生相互作用,降低药物清除率。红霉素似乎也会增加那些排泄大量还原型地高辛代谢物患者的地高辛的生物利用度,这可能是由于破坏了负责形成这些化合物的肠内微生物群。这些被指控的大环内酯类抗生素不应与其他已知会受到它们代谢影响的药物同时使用,或者至少,联合使用应仅在仔细监测患者的情况下进行。
The macrolide antibiotics include natural members, prodrugs & semisynthetic derivatives. These drugs are indicated in a variety of infections & are often combined with other drug therapies, thus creating the potential for pharmacokinetic interactions. Macrolides can both inhibit drug metab in the liver by complex formation & inactivation of microsomal drug oxidising enzymes & also interfere with microorganisms of the enteric flora through their antibiotic effects. Over the past 20 yrs, a number of reports have incriminated macrolides as a potential source of clinically severe drug interactions. However, differences have been found between the various macrolides in this regard & not all macrolides are responsible for drug interactions. With the recent advent of many semisynthetic macrolide antibiotics it is now evident that they may be classified into 3 different groups in causing drug interactions. The first group (e.g. troleandomycin, erythromycins) are those prone to forming nitrosoalkanes & the consequent formation of inactive cytochrome P450-metabolite complexes. The second group (e.g. josamycin, flurithromycin, roxithromycin, clarithromycin, miocamycin & midecamycin) form complexes to a lesser extent & rarely produce drug interactions. The last group (e.g. spiramycin, rokitamycin, dirithromycin & azithromycin) do not inactivate cytochrome P450 & are unable to modify the pharmacokinetics of other cmpds. It appears that 2 structural factors are important for a macrolide antibiotic to lead to the induction of cytochrome P450 & the formation in vivo or in vitro of an inhibitory cytochrome P450-iron-nitrosoalkane metabolite complex: the presence in the macrolide molecules of a non-hindered readily accessible N-dimethylamino group & the hydrophobic character of the drug. Troleandomycin ranks first as a potent inhibitor of microsomal liver enzymes, causing a significant decr of the metab of methylprednisolone, theophylline, carbamazepine, phenazone (antipyrine) & triazolam. Troleandomycin can cause ergotism in patients receiving ergot alkaloids & cholestatic jaundice in those taking oral contraceptives. Erythromycin & its different prodrugs appear to be less potent inhibitors of drug metab. Case reports & controlled studies have, however, shown that erythromycins may interact with theophylline, carbamazepine, methylprednisolone, warfarin, cyclosporin, triazolam, midazolam, alfentanil, disopyramide & bromocriptine, decreasing drug clearance. The bioavailability of digoxin appears also to be increased by erythromycin in patients excreting high amounts of reduced digoxin metabolites, probably due to destruction of enteric flora responsible for the formation of these cmpds. These incriminated macrolide antibiotics should not be administered concomitantly with other drugs known to be affected metabolically by them, or at the very least, combined admin should be carried out only with careful patient monitoring.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 相互作用
已报告与 spiramycin 同时使用时,左旋多巴的血浆浓度降低。
Reduced plasma concentrations of levodopa have been reported when given with spiramycin.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 相互作用
作者报告了一名21岁女性患有先天性长QT综合症的病例,她出现了多次晕厥发作,其中至少一次是由扭转性室速引起的。这种突然的并发症归因于48小时内同时开具了螺旋霉素和美喹他嗪。尽管这两种药物属于可能触发这种心律失常的药物家族,但它们并不被认为是扭转性室速的易感因素。撤除这种治疗导致晕厥发作完全消退,随访两年,初始QTc间期显著缩短,尽管如此,它仍然比正常时间长。这个病例强调了这两种药物家族联合用药的潜在风险,尤其是在患有先天性长QT综合症的患者中。
The authors report the case of a 21 year old woman with a congenital long QT syndrome who had several syncopal attacks at least one of which was caused by torsades de pointes. This sudden complication was attributed to the simultaneous prescription of Spiramycine and Mequitazine over a 48 hour period. These two drugs are not considered to be predisposing factors for torsades de pointes despite the fact that they belong to two families of drugs which can trigger this type of arrhythmia. The withdrawal of this treatment led to the complete regression of the syncopal episodes with a follow-up of two years and a significant shortening of the initial QTc interval which remained, nevertheless, longer than normal. This case underlines the potential risks of drug associations of these two families of drugs, especially in patients with the congenital long QT syndrome.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
  • 解毒与急救
/SRP:/ 立即急救:确保已经进行了充分的中和。如果患者停止呼吸,请开始人工呼吸,最好使用需求阀复苏器、球阀面罩装置或口袋面罩,按培训操作。如有必要,执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果发生呕吐,让患者前倾或将其置于左侧(如果可能的话,头部向下)以保持呼吸道畅通,防止吸入。保持患者安静,维持正常体温。寻求医疗帮助。 /毒物A和B/
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
spiramycin在口服给药后人体的吸收情况良好。对健康青年男性成年人进行15-30 mg/kg bw的口服给药,在3-4小时内达到血浆峰浓度,血浆浓度为0.96-1.65 mg/l。静脉给药(7.25 mg/kg b.w.)后观察到较大的分布容积(Vdss 5.6 l/kg),表明组织分布广泛。生物转化似乎并不重要。胆汁排泄是主要的排泄途径;只有7-20%的口服剂量通过尿液排泄。已知spiramycin在肺和前列腺组织以及皮肤中达到较高的组织:血清浓度。
Spiramycin is well absorbed in humans after oral administration. Oral administration of 15-30 mg/kg bw to healthy young male adults resulted in peak plasma levels in 3-4 hours and plasma concentrations of 0.96-1.65 mg/l. After intravenous dosing (7.25 mg/kg b.w.) a large volume of distribution (Vdss 5.6 l/kg) was observed indicating extensive tissue distribution. Biotransformation did not appear to be important. Biliary excretion was the main route of excretion; only 7-20% of an oral dose was excreted in the urine. Spiramycin is known to achieve high tissue:serum concentrations in pulmonary and prostatic tissues, and in skin.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
spiramycin 妊娠期使用注意事项: spiramycin会通过胎盘传递给胎儿。孕妇每天服用2克spiramycin后,母体血清、脐带血和胎盘中的抗生素浓度分别为1.19微克/毫升、0.63微克/毫升和2.75微克/毫升。当母体剂量增加到每天3克时,浓度分别为1.69微克/毫升、0.78微克/毫升和6.2微克/毫升。根据这些结果,脐血与母体血清的比率为0.5。此外,在这些剂量下,spiramycin在胎盘中的浓度约为母体血清的2-4倍。 spiramycin可通过母乳分泌。母亲每天服用1.5克spiramycin,连续3天,婴儿的spiramycin血清浓度为20微克/毫升。这种浓度具有抑菌作用。
Spiramycin crosses the placenta to the fetus. Concns of the antibiotic in maternal serum, cord blood, & the placenta after a dosage regimen of 2 g/day were 1.19 ug/ml, 0.63 ug/ml, & 2.75 ug/ml, respectively. When the maternal dose was increased to 3 g/day, the levels were 1.69 ug/ml, 0.78 ug/ml, & 6.2 ug/ml, respectively. Based on these results, the cord:maternal serum ratio is approx 0.5. Moreover, at these doses, spiramycin is concentrated in the placenta with levels approx 2-4 times those in the maternal serum. ... Spiramycin is excreted into breast milk. Nursing infants of mothers receiving 1.5 g/day for 3 days had spiramycin serum concns of 20 ug/ml. This concn was bacteriostatic.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
spiramycin是一种对来自乳腺炎牛牛奶中的大多数微生物具有活性的大环内酯类抗生素。本工作研究了静脉注射、肌内注射和皮下给药后spiramycin在血浆和牛奶中的处置情况。12头健康奶牛按每种途径单次注射spiramycin,剂量为30,000 IU/kg。在注射后收集血浆和牛奶。采用高效液相色谱法测定血浆中spiramycin浓度,采用微生物法测定牛奶中spiramycin浓度。静脉给药后的平均滞留时间在牛奶中明显长于血浆(20.7±2.7 h)(P<0.01)。从面积浓度-时间曲线计算出平均乳-血比值为36.5±15。对几个药代动力学参数进行了研究,以确定两种非血管途径的生物等效性。肌内或皮下给药后吸附的剂量分数几乎为100%,对于非血管途径是生物等效的,但是两种途径的吸收速率、最高浓度和达到最高浓度的时间存在显著差异。牛奶中排泄的spiramycin量在两种非血管途径之间没有差异,但是后者在牛奶中最高浓度的生物等效性不同。然而,这两种途径在牛奶浓度超过各种引起乳腺感染的病原体的最小抑菌浓度(MIC)的时间方面是生物等效的。
/MILK/ Spiramycin is a macrolide antibiotic that is active against most of the microorganisms isolated from the milk of mastitic cows. This work investigated the disposition of spiramycin in plasma & milk after iv, intramuscular & subcutaneous admin. Twelve healthy cows were given a single injection of spiramycin at a dose of 30,000 IU/kg by each route. Plasma & milk were collected post injection. Spiramycin concn in the plasma was determined by a high performance liquid chromatography method, & in the milk by a microbiological method. The mean residence time after iv admin was significantly longer (P<0.01) in the milk (20.7 +/- 2.7 h) than in plasma (4.0 +/- 1.6 h). An average milk-to-plasma ratio of 36.5 +/- 15 was calculated from the area concn-time curves. Several pharmacokinetic parameters were examined to determine the bioequivalence of the two extravascular routes. The dose fraction adsorbed after intramuscular or subcutaneous admin was almost 100% & was bioequivalent for the extravascular routes, but the rates of absorption, the max concns & the time to obtain them differed significantly between the two routes. Spiramycin quantities excreted in milk did not differ between the two extravascular routes but the latter were not bioequivalent for max concn in the milk. However, the two routes were bio-equivalent for the duration of time the milk concn exceeded the minimal inhibitory concn (MIC) of various pathogens causing infections in the mammary gland.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
血浆蛋白结合率从10%到25%。口服剂量600万单位在1.5到3小时后达到峰值血药浓度3.3微克/毫升;半衰期大约为5到8小时。组织中的高浓度可以在血浆浓度降至低水平后长时间维持。
Plasma protein binding ranges from 10 to 25%. An oral dose of 6 million units produces peak blood concentrations of 3.3 ug/mL after 1.5 to 3 hours; the half life is about 5 to 8 hours. High tissue concentrations are achieved and persist long after the plasma concentration has fallen to low levels.
来源:Hazardous Substances Data Bank (HSDB)