高三尖杉酯碱在大鼠及小鼠的代谢

本文报告³H-高三尖杉酯碱在正常大鼠、小鼠和荷瘤小鼠体内的吸收、分布和排泄。给大鼠静注后,t_1/2(α)和(β)分别为2.1和53.7分钟。静注后15分钟,以骨髓、肾和肝的放射性最高。荷瘤小鼠体内的放射性分布情况与正常大鼠的趋势相仿。静注后24小时,自大鼠尿排泄剂量的42.2%,在粪中排出6.3%,其中原形药放射性占剂量的15.9%。静注后48小时,自胆汁排泄剂量的57.7%,其中原形药放射性占剂量的20.2%。该碱经肌注也可被迅速吸收入血。     

葛根有效成分的代谢研究——Ⅱ.14C-黄豆甙元在大鼠体内的吸收、分布和消除

本文采用纸片液体闪烁计数法研究了¹⁴C-黄豆甙元在大鼠体内的吸收、分布和消除。大鼠口服¹⁴C-黄豆甙元30分钟,血液即可测出放射性,6～8小时达高峰,以后缓慢下降。口服给药吸收不完全,由实验推论约有64.6%放射性可被吸收。静脉注射后,血放射性消失曲线分为快、慢两个时相,其生物半衰期分别为13分钟和42分钟。放射性在肾、肝含量最高,血浆、肺、心次之,肌肉、脾、睾丸、脑较低。静脉注射后,¹⁴C主要自尿排出(24小时可排出剂量的71.2%),自粪排出17.4%。口服后24小时可自尿排出34.3%,自粪排出33.1%。胆汁也是一条重要排泄途径,静脉注射后24小时可自胆汁排出剂量的47.4%;口服后相应时间内排出39.1%。本文所得结果与前文应用化学方法所得结果进行比较,表明自消化道、尿、胆汁所回收的放射性主要是黄豆甙元的代谢产物,说明该药在体内的代谢很旺盛。     

三尖杉酯碱的代谢

本文报告³H-三尖杉酯碱在正常及肿瘤鼠体内的吸收、分布和排泄。静脉注射³H-三尖杉酯碱后,大鼠血中放射性迅速降低,快、慢两相的生物半衰期分别为3.5分钟和50分钟。给大鼠静脉注射³H-三尖杉酯硷,注射后15分钟时,药物在各组织中的分布以肾脏为最高,肝、骨髓、肺、心脏、胃肠、脾、肌肉次之,睾丸、血及脑较低。两小时后各组织中的药物浓度均迅速下降,但骨髓的下降较慢,在所有组织中药物浓度居于首位。24小时后则在所测组织中药物浓度均降到相当低的水平。³H-三尖杉酯碱在肿瘤小鼠体内的分布情况与正常大鼠的分布趋势大致相仿。³H-三尖杉酯碱在静脉注射后24小时自大鼠体内排出的总放射性,在尿相当于注射剂量的30.2%,在粪相当于16.6%,其中原型药共占14.5%。此外胆汁也是一条重要排泄途径。静脉注射后24小时可自胆汁排出剂量的24.5%,其中原型药占17.1%。该硷口服给药可迅速吸收入血,但吸收不完全。     

~3H-莪术醇在正常大鼠及肿瘤小鼠体内的代谢研究

~8H-莪术醇自大鼠胃肠道吸收迅速且完全。灌胃后5分钟血中即有放射性,15分钟达高峰,1小时仍保持较高浓度,放射性自血中消失的生物半衰期为11.5小时(t_(1/2)β)。静脉注射后血中放射性的消失分快、慢两相,生物半衰期分别为33分钟(t_(1/2)α)及12.5小时(t_(1/2)β)。 放射性在正常大鼠体内分布情况与肿瘤小鼠者相似。肝及肾组织含量约为其它组织的2～2.5倍。肿瘤组织中的分布与其它组织无明显差别;组织中放射性的消失与血浆中者略呈平行关系。放射性与脂肪组织似有较强的亲和力,给药后4小时仍维持较高水平。 放射性主要自尿排泄,口服或静脉注射后24小时分别自大鼠尿排出剂量的45.38％及51.91％。胆汁为另一排泄途径,大鼠口服或静脉注射后24小时,分别自胆汁排出36.47％及56.43％,而口服或静脉注射后72小时仅从粪回收6.77％及14.35％,可见,自胆汁排出的放射性大部分均又被重吸收入血。     

葛根有效成分的代谢研究——Ⅲ.葛根素的代谢及其药代动力学分析

本文建立了一个用薄层及紫外光分光光度法分离并测定生物样品中葛根素的方法,并用该法研究了葛根素在大鼠体内的代谢,分析了其药代动力学特点,并观察了口服后在人体的排泄情况。大鼠静脉注射后药物在肾脏含量较高,血浆、肝、脾次之,药物可通过血脑屏障进入脑组织,但脑中含量较低。血浆药-时曲线分快、慢两个时期。根据开放形二室模型数学公式计算葛根素各药代动力学参数为:t_1/2(α)=3.0分,t_1/2(β)=18.0分,V₁=19.9 ml,V₂=33.7ml,V_d=53.7ml,α=0.23/分,β=0.04/分,K₁₂=0.08/分,K₂₁=0.09/分,K₀=0.10/分,清除率=2.0 ml/分。此结果表明葛根素在体内分布广、消除快、不易积畜。体外实验证明,葛根素可被大鼠血及肝、肾等组织所代谢,且可与肝、肾、肺及血浆蛋白相结合,其与血浆蛋白的结合率达24.6%。大鼠灌胃葛根素后药物吸收较快,但吸收程度较差,灌胃后24小时自粪及胃肠道内容物回收的药物为剂量的37.3%。体外实验证明,葛根素在胃肠道内破坏很少。大鼠灌胃葛根素后24小时自尿及粪分别排出1.85%及35.70%,静脉注射后分别自尿、粪及胆汁排出剂量的37.62%,7.39%及3.65%。正常成人口服葛根素后36小时仅有0.78%自尿排出,72小时自粪排出剂量的73.3%。本文对葛根素及黄豆甙元的代谢特点进行了讨论。     

治疗血吸虫病新药硝硫氰胺的代谢研究

硝硫氰胺是一非锑类治疗血吸虫病的新药。在动物和人体研究了该药的代谢。家兔口服给药后4小时达到高峰血浓度。由二室模型对血浓度数据作药物动力学参数计算,得t_1/2ka、t_1/2)α和t_(1/2)β分别为0.815,0.924和105.8小时,Kel、K₂₁和K₁₂分别为0.0127、0.398和0.356小时^-1,V_f为0.934升。大鼠口服给药后4小时药物在各组织的浓度大小依次为:肝、肾、脾、肺、肌肉、心、脑和血。血吸虫浓度高于肝和血浓度,而且雌虫高于雄虫。该药由尿和胆汁排泄,大鼠一次口服的尿排泄持续3天以上,人连服三次排泄持续超过19天。尿代谢产物由层析、高速液相色谱、紫外光谱和化学方法检测,硝硫氰胺转化成氨基物再转化成N-葡萄糖醛酸甙,这种代转变化是其生物转化途径之一。     

葛根有效成分的代谢研究——Ⅱ.~(14)C-黄豆甙元在大鼠体内的吸收、分布和消除

本文采用纸片液体闪烁计数法研究了~(14)C-黄豆甙元在大鼠体内的吸收、分布和消除。大鼠口服~(14)C-黄豆甙元30分钟,血液即可测出放射性,6～8小时达高峰,以后缓慢下降。口服给药吸收不完全,由实验推论约有64.6％放射性可被吸收。静脉注射后,血放射性消失曲线分为快、慢两个时相,其生物半衰期分别为13分钟和42分钟。放射性在肾、肝含量最高,血浆、肺、心次之,肌肉、脾、睾丸、脑较低。静脉注射后,~(14)C主要自尿排出(24小时可排出剂量的71.2％),自粪排出17.4％。口服后24小时可自尿排出34.3％,自粪排出33.1％。胆汁也是一条重要排泄途径,静脉注射后24小时可自胆汁排出剂量的47.4％;口服后相应时间内排出39.1％。 本文所得结果与前文应用化学方法所得结果进行比较,表明自消化道、尿、胆汁所回收的放射性主要是黄豆甙元的代谢产物,说明该药在体内的代谢很旺盛。     

3H羟基斑蝥胺的药物代谢动力学研究

将氚标记的羟基斑蝥胺在大鼠体内研究了药物代谢动力学。所得血药浓度-时间数据依一定程序在709电子计算机上拟合曲线,并计算有关参数。结果表明,静脉注射后符合二房室开放型模型,其药代动力学参数为:t1/2α0.067hr,t1/2β2.208hr,V_d(面积)1.237l/kg,V₁0.264l/kg,K_el1.470 hr^-1,清除率0.388l/hr/kg。灌胃后可以单室开放型模型描述,其药代动力学参数为:K_α2.990hr^-1,K_el0.257hr^-1,V_d1.603l/kg,t1/22.693hr,t_max0.90hr,C_max0.745μg/ml,F94.15%。尚将本药以静脉和灌胃两种途径给药后直接观察在大鼠体内的组织分布和在尿粪胆汁中的排泄,结果表明本药分布广,主要经肾排泄,且排泄较快,与药代动力学分析结果相一致。     

黄花夹竹桃次甙乙的药代动力学研究

本文研究[³H]标记的黄花夹竹桃次甙乙(Neriifolin简称次甙乙)在大鼠体内的药代动力学。静脉注射后[³H]-次甙乙在血浆中的消除半衰期(T_1/2β)为5天,分布容积(Vd)为15.3L/kg。药物的主要分布在肝脏、胆汁和胃肠道内。灌胃给药吸收迅速完全,30 min血药浓度即达高峰。无论静脉注射或灌胃后,放射性主要从粪中排出,尿中较少,排出形式主要是代谢产物。[³H]-次甙乙与血浆蛋白的结合为91.7%。结果表明:次甙乙在大鼠体内的药代动力学特点与一般亲脂性强心甙相似。     

两种测定小鼠体内力达霉素药代动力学方法的比较

目的对测定小鼠血清浓度的总放射性方法和经过高效液相色谱分离后再测定放射性的两种方法进行比较。方法首先对力达霉素进行同位素标记并且分离纯化。给小鼠尾iv ¹²⁵I-力达霉素(100 μg·kg^-1)，采集血样，样品经两种方法测定。对得到的药代动力学参数进行统计学处理。结果两种方法测定得到的药代动力学参数(V_d, t_1/2α, t_1/2β, k₂₁, k₁₀, k₁₂, AUC和CL) 存在显著性的差异 (P<0.05)。结论采用色谱分离后再测定¹²⁵I-力达霉素原形的放射性较为合理和准确。     

3H-乙炔雌二醇环戊醚的吸收、分布和排泄

给雌大鼠口服氚标记的乙炔雌二醇环戊醚(EECPE)后半小时血液中即可测出放射性,但10小时后才达高峰。在胃肠道的生物半衰期为13小时,说明³H-EECPE的吸收较慢。猴服³H-EECPE后1小时血液即可测出放射性,4小时达高峰。³H-EECPE被吸收后,在大鼠和猴体内的分布均以脂肪组织的浓度最高,脑组织的浓度也较高,而在靶器官—子宫、输卵管、乳腺—的浓度却不高。³H-EECPE在各组织中均有较长时间的储留,尤其在脂肪组织中储留的时间更长,这可以解释其口服后的长效作用。³H-EECPE的主要排泄途径为粪,自尿排出较少。由于在体内储留,所以排泄缓慢。     

Pharmacokinetics in Rat of 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), a Drinking Water Mutagen,after a Single Dose

Abstract: The pharmacokinetics of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) was evaluated after a single oral or intravenous administration in the rats using ¹⁴C-labelled compound. Twenty to 35% of the dose was absorbed into circulation from the gastrointestinal tract as assessed from the excretion in urine. The mean elimination half-life of the radioactivity in blood (T_1/2 k₁₀) was 3.8 hr. Traces of radioactivity remained in the blood for several days. The tissues lining the gastrointestinal and urinary tract, kidneys, stomach, small intestines and urinary bladder contained the highest radioactivity. The activity declined slowest in the kidneys. Urine was the main excretion route. Seventy-seven % of the total amount excreted appeared in urine in 12 hr and 90% in 24 hr. No radioactivity was exhaled in air suggesting that elimination through respiration did not occur. After an intravenous administration of ¹⁴C-MX, the T_1/2 k₁₀, was much longer, 22.9 hr, and the total elimination half-life (T_1/2 β), 42.1 hr. The results indicate that MX is absorbed from the gastrointestinal tract to a considerable degree and it is excreted in urine very rapidly. A fraction of MX or its metabolites is retained in blood for a longer period of time. The pharmacokinetics of MX does not suggest extensive cumulation of MX in tissues after continuous exposure.     

Disposition and metabolism of a novel diurea inhibitor of acyl CoA: cholesterol acyltransferase (YM17E) in the rat and dog

We have investigated the disposition and metabolism of YM17E after intravenous and oral administration in the rat and dog.

2. Unavailability of YM17E was 5–9% at oral doses of 3–30 mg/kg in rat, and 9 and 13% at oral doses of 10 and 30mg/kg in dog.

3. Five N-demethylated metabolites, which have significant pharmacological activity, were found in rat and dog plasma after oral administration. Plasma concentrations of each of these metabolites were comparable with (hat of unchanged drug.

4. When ¹⁴C-YM17E was administered to rat, AUC of unchanged drug was 7% of that of radioactivity. However, AUC of the combined concentration of unchanged drug and five active metabolites was about 50% of that of radioactivity, indicating that the pharmacological activity of the agent was maintained in spite of its biotransformation.

5. After oral administration of ¹⁴C-YM17E at a dose of 10 mg/kg to rat, radioactivity was distributed widely to almost all tissues except the brain. The concentration of radioactivity in the liver, one of the target organs, was 65 times higher than that in plasma at 1 h after administration.

6. A significant amount of radioactivity in the liver was located in the microsomal subfraction, which contains much acyl CoA: cholesterol acyl transferase activity. More than 50% of this microsomal radioactivity was derived from unchanged YM17E and five active metabolites.

7. From excretion data in the bile duct-cannulated rat, the absorption ratio of YM17E from the gastrointestinal tract in this species was estimated to be at least 40%, suggesting that the low bioavailability of the drug is due to extensive first-pass metabolism.

8. Some 95% of the administered radioactivity was excreted in the faeces of rat following iv or po doses of ¹⁴C-YM17E.     

The Distribution of 14C–Chloramphenicol in the Japanese Quail (Coturnix coturnix japonica)

Abstract: The distribution of ¹⁴C–labelled chloramphenicol after oral and intravenous administration to egg laying Japanese quail was studied by whole–body autoradiography. In the liver, kidneys, gizzard, intestinal contents (bile) and oviduct, the ¹⁴C–concentration was higher than that of the blood short time after injection and remained higher than the blood up to 4 days. From 4 hrs, the concentration of ¹⁴C in the egg yolks was higher than that of the blood and from 24 hrs the radioactivity in the albumen of the eggs in the oviduct was also higher than that of the blood. The peak concentration in the egg yolk was found in the second egg laid 2–4 days after administration of ¹⁴C–chloramphenicol. In the albumen the maximum concentration was found in the first laid egg 24–48 hrs after administration. In the egg yolks, about 30% of the radioactivity represented unchanged chloramphenicol up to 5 days after administration. It was also shown that about 5% of the injected ¹⁴C–chloramphenicol was exhaled as ¹⁴CO₂ during the first 12 hrs and about 37% of the dose was excreted in the combined faeces and urine during the same period of time     

Absorption,metabolism and excretion of darexaban (YM150), a new direct factor Xa inhibitor in humans

1.?The absorption, metabolism and excretion of darexaban (YM150), a novel oral direct factor Xa inhibitor, were investigated after a single oral administration of [¹⁴C]darexaban maleate at a dose of 60?mg in healthy male human subjects.

2.?[¹⁴C]Darexaban was rapidly absorbed, with both blood and plasma concentrations peaking at approximately 0.75?h post-dose. Plasma concentrations of darexaban glucuronide (M1), the pharmacological activity of which is equipotent to darexaban in vitro, also peaked at approximately 0.75?h.

3.?Similar amounts of dosed radioactivity were excreted via faeces (51.9%) and urine (46.4%) by 168?h post-dose, suggesting that at least approximately half of the administered dose is absorbed from the gastrointestinal tract.

4.?M1 was the major drug-related component in plasma and urine, accounting for up to 95.8% of radioactivity in plasma. The N-oxides of M1, a mixture of two diastereomers designated as M2 and M3, were also present in plasma and urine, accounting for up to 13.2% of radioactivity in plasma. In faeces, darexaban was the major drug-related component, and N-demethyl darexaban (M5) was detected as a minor metabolite.

5.?These findings suggested that, following oral administration of darexaban in humans, M1 is quickly formed during first-pass metabolism via UDP-glucuronosyltransferases, exerting its pharmacological activity in blood before being excreted into urine and faeces.     

N-[C14]甲酰溶肉瘤素在肿瘤病人的吸收和排泄

精原细胞瘤病人口服N[C¹⁴]-甲酰溶肉瘤素15毫克(约30微居里)后72小时内,C¹⁴自尿及大便的总排出量为剂量的68.0-77.4%;其中由尿及大便所排出的放射性各约半量.尿中的放射性绝大部分为给药后前5小时内排出的,大便中的放射性则主要在给药后48小时(两次大便,便秘患者除外)内排出.在服药后24小时内,血液(全血、血浆及血球)、唾液及呼出的二氧化碳仅有痕迹量放射性存在.口服N-甲C¹⁴的同时,口服大量非标记的N-甲,并未显著地影响C¹⁴的排泄.     

Biodistribution and metabolism in rats and mice of bucromarone.

The metabolism and disposition of bucromarone, labeled with 14C on the chromone group, has been investigated in C3H mice and Wistar rats. In separate experiments, animals received 4.4 mmol/kg, iv or po, [14C]bucromarone hydrochloride or succinate. More than 90% of the administered radioactivity was excreted in bile, after iv and po administration. Less than 5 min after iv injection, radioactivity concentrated in all tissues, and blood concentration became very low as compared with its initial level. After po administration, no more than 10% of the dose was incorporated in the tissues. The discrepancy between the high biliary excretion and the low tissue and blood concentration after po administration suggested that bucromarone was well absorbed through the gastrointestinal tract; but after liver uptake, drug and its metabolites were excreted in the bile, less than 10% being distributed into the extrahepatic blood. Comparison of the iv and po areas under the plasma 14C-radioactivity concentration-time curves indicated a poor bioavailability of the molecule after po administration. Analysis of the radioactivity content of bile showed that bucromarone was extensively metabolized after both administration routes. Unchanged bucromarone and three main metabolites, monodesbutylbucromarone, didesbutyl bucromarone, and 2-(3-5-dimethyl-4-hydroxybenzoyl) chromone, amounting to 85% of the bile radioactivity, were identified by HPLC and mass spectrometry. These findings are consistent with a dealkylation of the N-dibutyl group, yielding potential pharmacologically active metabolites monodesbutyl and didesbutyl bucromarone.     

The Disposition and Metabolism of Amodiaquine in Small Mammals

1. 7-Chloro-4-(3′-diethylamino-4′-hydroxyanilino)quinoline (amodiaquine) labelled with ¹⁴C has been synthesized and administered in single doses to rats including bile-duct-cannulated rats, to guinea-pigs and to mice, by oral or parenteral routes.

2. Amodiaquine was extensively and rapidly absorbed from the rat intestinal tract. Excretion of total radioactivity from rats and guinea pigs was slow and prolonged and was <50% dose in 9 days. Excretion of ¹⁴C was predominantly in faeces of rats after oral and i.p. dosage, and guinea-pigs after i.p. dosage. Radioactivity in rat and guinea-pig urine was <11% dose.

3. Biliary excretion of ¹⁴C following oral or i.v. dosage to rats was 21% dose in 24?h.

4. Amodiaquine was extensively metabolized and conjugated with <10% dose excreted unchanged in urine or bile. Two major basic metabolites in rat urine were tentatively identified as the mono- and bis-desethyl amines.

5. 7-Chloro-4-(4′-diethyl-1′-methylbutylamino)quinoline (chloroquine) was excreted largely unchanged in urine of rats after oral or parenteral administration of single doses, with <5% dose excreted in rat bile in 24?h.