利培酮和氯氮平及其代谢产物对体外培养大鼠胰岛分泌功能的影响

近年来关于非典型抗精神病药(AAPDs)对糖代谢影响的报道和临床研究很多.AAPDs中氯氮平对糖代谢影响最大[1],利培酮影响较小,介于氯氮平、奥氮平和传统抗精神病药之间[2].     

临床治疗剂量氯氮平人体内代谢机制研究

目的本课题主要探讨临床治疗剂量氯氮平的代谢机制，为临床合理用药提供指导。方法15例精神分裂症男性住院病人，单用氯氮平治疗，达到稳态浓度后，采用自身前后对照设计试验，研究氟西汀抑制前后氯氮平及其代谢产物药代动力学参数的变化及其与酶活性的相关性。CYP1A2、CYP3A4和CYP2136的活性分别用咖啡因、咪达唑仑和右美沙芬探测。体内氯氮平及其代谢产物、咪哒唑仑及其代谢产物、尿中右美沙芬及其代谢产物用HPLC-MS测定。血中咖啡因及其代谢产物用HPlC-UV测定。数据用SPSS软件进行统计分析。结果氯氮平合用氟西汀后，氯氮平的Cmax、AUC0-24显著增加，t1/2增加趋势，但没有显著性差异。代谢产物去甲氯氮平的AUC0-24显著降低，Cmax和t1／2无显著性差异。N-氧化氯氮平的Cmax和AUC0-24显著性降低，t1／2没有显著性差异。合用氟西汀前后CYP1A2活性无差异，CYP3A4和CYP2D6活性显著降低。合用氟西汀前后CYP1A2活性分别与合用氟西汀前后氯氮平的AUC0-24以及去甲氯氮平的AUC0-24相关，与N-氧化氯氮平的AUC0-24无显著相关。CYP3A4和CYP2D6活性与氯氮平、去甲氯氮平、N-氧化氯氮平的AUC0-24均无显著相关，但是合用氟西汀后CYP3A4活性变化与N-氧化氯氮平的AUC0-24变化显著相关，CYP2D6活性变化与去甲氯氮平的AUC0-24变化显著相关。结论临床剂量氯氮平的代谢途径为去甲基化和N-氧化，其中去甲基代谢为主要代谢途径主要由CYP1A2催化。CYP3A4和CYP2D6不是催化CLZ代谢的主要酶，但是CYP3A4参与了CLZN-氧化代谢，CYP2D6参与去甲基代谢。     

MDMA在急性染毒大鼠死后体内的再分布

目的:探索死后MDMA再分布变化规律及温度对死后MDMA再分布的影响。方法:将急性染毒大鼠处死后,分别置于室温下(17℃)或冷藏(4℃)。并于死后0 h2、h、24 h、48 h采集心血、外周血及心肌、肝、脾、肺组织,用液-液萃取衍生化法和气相色谱-氮磷检测器(GC-NPD)检测MDMA含量。结果:大鼠死后48 h内,随死亡时间延长,室温下心血MDMA浓度呈升高趋势(P<0.05),肝MDMA浓度先升后降(P<0.05),心肌MDMA浓度无显著性变化(P>0.05)。在死后2-24 h内,脾MDMA浓度升高(P<0.05),肺MDMA浓度下降(P<0.05)。冷藏下血液中MDMA变化幅度较小(P<0.01);组织MDMA浓度在室温和冷藏下比较差异无显著性(P>0.05)。结论:MDMA在大鼠体内存在死后再分布现象,死后血药浓度在低温下较高温下稳定。     

急性吗啡肌注大鼠死后体内吗啡再分布的免疫组化研究

本文采用免疫组化法对治疗量及中毒量吗啡注射大鼠死后体内吗啡的定位及分布变化分别进行研究。发现：⑴吗啡广泛分布于大脑皮质、海马回、基底核、丘脑、脑干、扣带回、嗅束、胼胝体及小脑神经细胞胞浆内及神经纤维；心、肝、肾、睾丸及血管平滑肌等也有吗啡分布，但胸腺、淋巴结等未发现吗啡存在；⑵治疗量吗啡注射鼠死后９６ｈ内，心、肝、肾、肾上腺等大部分实质器官组织细胞中吗啡含量随死后时间延长而明显减少（Ｐ＜０．０１）；中毒量吗啡注射鼠死后１２ｈ内，组织细胞中吗啡含量变化甚微，但死后２４－９６ｈ，吗啡量缓慢递减（Ｐ＜０．０５）。骨骼肌吗啡量随死后时间延长而明显增加，死后４８ｈ内脑组织吗啡量无明显变化。本研究证实死后尸体内吗啡再分布的客观存在，探讨了吗啡再分布发生机制。免疫组化法为海洛因或吗啡成瘾及中毒死亡的医学检测提供了新的手段。     

甲状腺功能对地西泮及其代谢产物在大鼠体内代谢的影响

目的：研究甲状腺功能对地西泮及其代谢物的药代动力学影响。方法：采用HPLC技术，测定不同甲状腺功能状态时，大鼠血液中地西泮及其体内主要代谢产物去甲基地西泮的浓度。结果：甲亢组大鼠地西泮在体内消除加速，峰浓度下降，AUC减少，消除T1/2缩短。甲减组大鼠则消除减慢，峰浓度增高，AUC增大，消除孔。延长。而其主要代谢产物去甲地西泮的药动学参数则相反。结论：甲状腺功能提高时，大鼠对地西泮的代谢能力明显增加，消除加速；而甲腺功能降低则相反。     

咖啡因试验与氯氮平体内代谢的相关性

通过检测尿中咖啡因（Ｃａｆ）及其代谢产物,探讨细胞色素Ｐ４５０ １Ａ２（ＣＹＰ１Ａ２）与体内氯氮平（ＣＬＺ）去甲基代谢物的关系。方法单剂ｐｏ Ｃａｆ１５０ｍｇ,ｈ５末采取尿样,以Ｃａｆ代谢产物和Ｃａｆ的比值「（１７Ｘ＋１７Ｕ）／１３７Ｘ」反映ＣＹＰ１Ａ２活性。２ｄ后单剂ｐｏＣＬＺ１０ｍｇ,收集０－２４ｈ尿样。０－２４ｈ悄中ＣＬＺ剩余量占给药剂量的分率（ＣＬＺ％）反映ＣＬＺ清除;０－２４ｈ尿中去甲     

在线柱切换高效液相色谱法测定人血清中奥氮平、氯氮平和N-去甲氯氮平的浓度

目的：建立简单并能同时测定人血清中奥氮平、氯氮平及N-去甲氯氮平的血药浓度方法。方法：采用在线柱切换高效液相色谱法,紫外检测器检测,血清直接进样分析血清中奥氮平、氯氮平及N-去甲氯氮平的浓度。结果：奥氮平、氯氮平及N-去甲氯氮平均具有良好的专属性、线性、精密度、回收率和稳定性。结论：在线柱切换高效液相色谱法简单、准确,适用于奥氮平、氯氮平及N-去甲氯氮平血药浓度监测。此方法可以血清直接进样分析,省去了烦琐的预处理,同时保证检测的准确性。     

川芎嗪在兔体内代谢产物的研究

应用高效液相色谱法将川芎嗪在家兔血液中的代谢产物进行分离,对原药及两种代谢产物进行了紫外、红外、质谱、核磁共振等光谱分析,推断出川芎嗪代谢产物的结构,并用化学方法合成了代谢物对照品,对其结构进一步得到验证。     

精神障碍患者合并用药对氯氮平血药浓度的影响研究

目的 考察合并用药对精神障碍患者氯氮平血药浓度的影响,为临床合理用药提供参考。方法 选取聊城市第四人民医院精神科2019年1月至2021年5月收治的需用氯氮平控制症状的100例精神障碍患者,根据其临床症状分别在氯氮平治疗的基础上合用普萘洛尔、丙戊酸钠、利培酮、碳酸锂和奥氮平5种药物治疗。依据合并用药种类将研究数据分为五组,每组各观察20例患者。分别于合并用药前、合并用药1周后,采用高效液相色谱法（HPLC）测定并比较精神障碍患者体内氯氮平、去甲氯氮平的血药浓度,分析合并用药对氯氮平血药浓度的影响。结果 普萘洛尔、丙戊酸钠、碳酸锂合并用药1周后与合并用药前比较,氯氮平、去甲氯氮平的血药浓度差异有统计学意义（P <0.05）;利培酮、奥氮平合并用药1周后与合并用药前比较,氯氮平、去甲氯氮平的血药浓度差异无统计学意义（P> 0.05）。结论 在精神科内部分常用的药物对氯氮平的血药浓度存在不同程度的影响,临床合并用药时应定期监测氯氮平的血药浓度,及时调整患者氯氮平的服用剂量,使其在有效浓度范围内,避免不良反应的发生,促进其安全、合理用药。     

Postmortem tissue distribution of morphine and its metabolites in a series of heroin‐related deaths

The abuse of heroin (diamorphine) and heroin‐related deaths are increasing around the world. The interpretation of the toxicological results from suspected heroin‐related deaths is notoriously difficult, especially in cases where there may be limited samples. To help forensic practitioners with heroin interpretation, we determined the concentration of morphine (M), morphine‐3‐glucuronide (M3G), and morphine‐6‐glucuronide (M6G) in blood (femoral and cardiac), brain (thalamus), liver (deep right lobe), bone marrow (sternum), skeletal muscle (psoas), and vitreous humor in 44 heroin‐related deaths. The presence of 6‐monoacetylmorphine (6‐MAM) in any of the postmortem samples was used as confirmation of heroin use. Quantitation was carried out using a validated liquid chromatography–tandem mass spectrometry (LC–MS/MS) method with solid‐phase extraction. We also determined the presence of papaverine, noscapine and codeine in the samples, substances often found in illicit heroin and that may help determine illicit heroin use. The results of this study show that vitreous is the best sample to detect 6‐MAM (100% of cases), and thus heroin use. The results of the M, M3G, and M6G quantitation in this study allow a degree of interpretation when samples are limited. However in some cases it may not be possible to determine heroin/morphine use as in four cases in muscle (three cases in bone marrow) no morphine, M3G, or M6G were detected, even though they were detected in other case samples. As always, postmortem cases of suspected morphine/heroin intoxication should be interpreted with care and with as much case knowledge as possible.     

Pharmacokinetics of theobromine and its metabolites in rabbits

The pharmacokinetics of theobromine (3, 7-DMX) and its metabolites was investigated in detail in four male rabbits after bolus intravenous injection (4 mg/kg) of the compound. Apparent first-order rate constants for the metabolic processes involved in the formation of 3,7-DMX metabolites and their excretion in urine were calculated. Theobromine, 7-methylxanthine (7-MX) and 3-methylxanthine (3-MX) were measured in blood and urine, and the other metabolites were determined only in urine. An appropriate model of 14 compartments is formulated to describe the disposition of 3,7-DMX and its metabolites.     

Pharmacokinetics and distribution of schisandrol A and its major metabolites in rats

1.?Schizandrol A is an active component in schisandra, also the representative component for the identification of schisandra.

2.?A rapid resolution liquid chromatography coupled with quadruple–time–of–flight mass spectrometry (RRLC–QTOF/MS) was developed to investigate the pharmacokinetics of schizandrol A after its intragastric administration (50?mg/kg) in rats.

3.?Schizandrol A was rapidly absorbed (T _max = 2.07?h), with a longer duration (t _1/2 = 9.48?h) and larger apparent volume of distribution (Vz/F?=?111.81?l/kg) in rats. Schizandrol A can be detected in main organs and the order of its distribution was in the liver?>?kidney?>?heart?>?spleen?>?brain, particularly higher in the liver.

4.?Five schizandrol A metabolites were identified, including 2–demethyl–8(R)–hydroxyl–schizandrin, 3–demethyl–8(R)–hydroxyl–schizandrin, hydroxyl–schizandrin, demethoxy–schizandrin, 2, 3–demethyl–8(R)–hydroxyl–schizandrin, indicating that the hydroxylation and demethylation may be the major metabolic way of schizandrol A.

5.?This study defined the pharmacokinetic characteristics of schizandrol A in vivo, and the RRLC–QTOF/MS is more sensitive and less limited by conditions, and needs less samples, which may be a useful resource for the further research and development of schisandrol A.     

Pharmacokinetics of theobromine and its metabolites in rabbits

The pharmacokinetics of theobromine (3, 7-DMX) and its metabolites was investigated in detail in four male rabbits after bolus intravenous injection (4 mg/kg) of the compound. Apparent first-order rate constants for the metabolic processes involved in the formation of 3,7-DMX metabolites and their excretion in urine were calculated. Theobromine, 7-methylxanthine (7-MX) and 3-methylxanthine (3-MX) were measured in blood and urine, and the other metabolites were determined only in urine. An appropriate model of 14 compartments is formulated to describe the disposition of 3,7-DMX and its metabolites.     

Pharmacokinetics of theophylline and its metabolites in rabbits

The pharmacokinetics of theophylline (1,3-DMX) and its metabolites were investigated in detail in four male rabbits after bolus intravenous injection (12 mg/kg) of the compound. Theophylline was measured in blood and urine, and its metabolites were determined only in urine. Apparent first-order rate constants for the metabolic processes involved in the formation of 1,3-DMX metabolites and their excretion in urine were calculated. An appropriate 13-compartment model was formulated to describe the disposition of 1,3-DMX and its metabolites.     

Postmortem distribution of tramadol, amitriptyline, and their metabolites in a suicidal overdose

A case report involving a 34-year-old white male who was found dead at home by his roommate is presented. At the time of his death, he was being treated with tramadol/acetaminophen, metaxalone, oxycodone, and amitriptyline. The decedent's mother stated that he had been taking increasing amounts of pain medication in order to sleep at night. There were no significant findings at autopsy; however, toxicology results supported a cause and manner of death resulting from suicidal mixed tramadol and amitriptyline toxicity. This case reports the tissue and fluid distribution of tramadol, amitriptyline, and their metabolites in an acutely fatal ingestion in an effort to document concentrations of these analytes in 12 matrices with respect to one another to assist toxicologists in difficult interpretations.     

Gender differences in plasma clozapine levels and its metabolites in schizophrenic patients

Forty refractory schizophrenic patients (21 females and 19 males) participated in a fixed-dose study with clozapine. After a 6-week trial of haloperidol and a 1-week washout time period, non-responding patients were placed on clozapine and the dosage titrated up to 400 mg/day for the next 5 weeks. Plasma clozapine levels and its two metabolites desmethylclozapine (DCLOZ) and clozapine N-oxide (CNO) were measured at weeks 2, 4 and 6. Blood samples were obtained 10–12 h post-evening dose and prior to the morning dose. Clozapine and its metabolites were assayed by HPLC with UV detection. Patients were assessed for clinical response with the Brief Psychiatric Rating Scale (BPRS) at baseline and at weeks 2, 4 and 6. BPRS scores were also divided into positive (+) and negative (−) symptoms subscales. Plasma clozapine and DCLOZ levels were significantly lower in males. Plasma CNO levels were slightly lower in males but it was not statistically significant. Decreased total BPRS, (+) and (−) symptoms subscale scores occurred during the study for both gender groups. A greater magnitude of change for the (−) symptom subscale score was observed in the male group. Gender was not a significant factor in the incidence or severity of side-effects. © 1997 John Wiley & Sons, Ltd.     

Postmortem instability of dopamine and its metabolites in rat striatum and limbic forebrain.

The level of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxytyramine (3-MT) were determined in the brains of rats kept 24 h after death at two different temperatures, 4 degrees C and 22 degrees C. The estimations were carried out in the striatum and limbic forebrain containing: nucleus accumbens, septum, limbic cortex, amygdala, tuberculum olfactorium. Brain tissue of control rats was dissected immediately after decapitation, frozen over solid CO2 and stored at -70 degrees C until assayed. DA and its metabolites were measured, using high-performance liquid chromatography (HPLC) with electrochemical detection. The levels of DA, DOPAC and HVA in the striatum were significantly decreased (from 50% to 80%) when rats were kept 24 h after death. The changes were more pronounced at 22 degrees C than at 4 degrees C. As the decrease in DA concentration was stronger than that of its final metabolite HVA, the ratio of HVA/DA concentration measured as an index of the rate of DA metabolism was even increased (from 8 to 11). Different changes occurred in the limbic region, where the levels of DA and HVA did not change neither at 4 degrees C nor 22 degrees C. The level of intraneuronally formed DA metabolite-DOPAC was elevated (by about 60%). The level of 3-MT, extraneuronally formed DA metabolite, was significantly increased both in the striatum (200%) and limbic DA structures (500%). These data demonstrate regional postmortal differences in stability of DA and its metabolite levels, which are in the striatum temperature-, time-, and storage-dependent. That implicates a careful assessment of postmortem studies when measuring the neurotransmitter dynamics in human necropsy material.     

Postmortem metabolomics: Correlating time‐dependent concentration changes of xenobiotic and endogenous compounds

Postmortem redistribution (PMR) describes the artificial postmortem concentration changes of xenobiotics that may pose major challenges in forensic toxicology. Only a few studies have systematically investigated time‐dependent postmortem drug concentration changes so far and the a posteriori estimation of the occurrence of PMR is not yet possible. In this context, the general concept that postmortem biochemical changes in blood might parallel drug redistribution mechanisms seems promising. Thus, the current study investigated the possible correlations between time‐dependent postmortem concentration changes of xenobiotic and endogenous compounds; exemplified for authentic morphine (n = 19) and methadone (n = 11) cases. Peripheral blood samples at two time‐points postmortem were analyzed for morphine and methadone concentrations and an (un)targeted postmortem metabolomics approach was utilized to combine targeted quantitative analysis of 56 endogenous analytes and untargeted screening for endogenous compounds (characterizing 1174 features); liquid and gas chromatography–mass spectrometry was used respectively. Individual statistically significant correlations between morphine/methadone and endogenous compounds/features could be determined. Hence, the general applicability of the proposed concept could successfully be confirmed. To verify the reproducibility and robustness of the correlating behavior, a larger dataset must be analyzed next. Once a marker/set of markers is found (e.g. robust correlation with specific xenobiotic or xenobiotic class), these could be used as surrogates to further study the time‐dependent PMR in a broader variety of cases (e.g. independent of a xenobiotic drug present). A crucial next step will also be the attempt to create a statistical model that allows a posteriori estimation of PMR occurrence of xenobiotics to assist forensic toxicologists in postmortem case interpretation.