胡柚提取物抑制硝苯地平肝微粒体酶代谢的研究

目的:探讨胡柚不同部位提取物对体外小鼠肝微粒体酶代谢活性的抑制效应。方法:在小鼠肝微粒体孵育体系中加入硝苯地平和胡柚不同部位的提取物后,应用HPLC法测定体系中硝苯地平的剩余含量。结果:硝苯地平的标准曲线方程为Y=2.136×10⁴X+2.334×10⁴（r=0.999 3）,线性范围:0.15～240 mg·L^-1。含有相同浓度硝苯地平及3种胡柚提取物的小鼠肝微粒体孵育体系中,柚汁、果肉、柚皮中剩余硝苯地平浓度分别为8.802,7.497,4.227mg·L^-1。结论:胡柚不同部位提取物对小鼠肝微粒体酶活性有抑制作用,尤其是柚汁和果肉部分活性较强。     

吡喹酮在大环内酯类抗生素和糖皮质激素诱导的大鼠肝微粒体中的代谢

我们的结果表明，只有经细胞色素P－450ⅢA1同功酶特异的诱导剂（红霉素和地塞米松）处置过的大鼠肝微粒体能显著地代谢吡喹酮（PQT），高铁氧化钾能破坏细胞色素P－450Fe(Ⅱ）－代谢物的复合物，使细胞色素P－450ⅢA1同功酶的活性恢复。因此，当微粒体和PQT的温孵体系中加入高铁氰化钾时，PQT在经多剂红霉素处置后的微粒体中的代谢速率进一步增加，而乙酰螺旋霉素诱导的细胞色素P－450并不形成复合物，因此，高铁氰化钾不影响PQT在经乙酰螺旋霉素处置后的微粒体中的代谢。三乙酰竹桃霉素作为细胞色素P－450ⅢA1的特异抑制剂，能抑制PQT在地塞米松处置过的肝微粒体内的代谢速率53％，以上结果表明，大鼠肝细胞色素P－450ⅢA1同功酶参与PQT在大鼠肝微粒体内的代谢。     

Inhibition of Human CYP3A Catalyzed 1′-Hydroxy Midazolam Formation by Ketoconazole,Nifedipine, Erythromycin,Cimetidine, and Nizatidine

Pharmaceutical Research -     

N-三甲基壳聚糖对硝苯地平片在犬体内药物动力学的影响

目的:研究N-三甲基壳聚糖(TMC60)对硝苯地平片药物动力学的影响。方法:以Beagle犬为实验动物,分别口服硝苯地平片Ⅰ(含TMC60)及硝苯地平片Ⅱ(不含TMC60),采用单剂量交叉实验,在预定的时间点取血样,测定硝苯地平的浓度,并用3P97软件包拟合两种片剂的药代动力学参数。结果:硝苯地平片Ⅰ、Ⅱ在犬体内均符合口服吸收二室模型。两种片剂的主要参数T_(max)、C_(max)、Ka、AUC等均有显著性差异(P<0.05)。结论:TMC60可显著改善硝苯地平在犬体内的吸收,提高其生物利用度,是一种较好的促进吸收的辅料。     

Inhibition of 1,2-Dimethylhydrazine Metabolism by Disulfiram

1. The effects of disulfiram on the metabolism of 1,2-dimethylhydrazine were studied in CDF rats.

2. Treatment with disulfiram causes enhanced elimination of azomethane in the expired air, inhibition of CO₂ production, and decreased levels of 1,2-dimethylhydrazine metabolites in the urine.

3. These results suggest that disulfiram inhibits the N-oxidation of azomethane to azoxymethane, thus preventing further metabolism to the ultimate carcinogenic species, and provide an explanation for the observations that disulfiram inhibits 1,2-dimethylhydrazine-induced neoplasia of the large intestine.     

Indomethacin Inhibition of Bumetanide Diuresis in Dogs

Abstract: Clearance experiments in conscious, trained, intact dogs and also a one minute urine collection in conscious, ureterostomized dogs show that indomethacin pretreatment significantly alters the renal haemodynamic end excretional effects of bumetanide. The haemodynamic parameters (inulin and PAH clearance) are significantly reduced during the time interval 10–40 minutes after bumetanide administration in indomethacin pretreated dogs. In the same conditions urine volume, and sodium and chloride excretion are reduced while potassium excretion is less influenced. Indomethacin pretreatment does not affect the abolition of the cortico-medullary electrolyte gradient caused by bumetanide administration. The results support evidence for an important role of prostaglandins in the diuretic effect of bumetanide.     

高效液相色谱法测定红霉素肠溶胶囊的含量

目的 建立测定红霉素肠溶胶囊含量的高效液相色谱法.方法 色谱柱为Diamonsil C18柱(250 mm×4.6 mm,5 μm),流动相为0.067 mol/L磷酸二氢铵溶液(用三乙胺调pH至6.5)-乙腈(58∶42),检测波长为210 nm,流速为1.0 mL/min,柱温为30℃.结果 质量浓度线性范围为20～ 140 g/L(r=0.999 9),平均加样回收率为100.14％,RSD为0.29％(n=6).结论 所用方法简便、准确、灵敏度高、重现性好,可用于红霉素肠溶胶囊的含量测定.     

紫外分光光度法测定红霉素肠溶胶囊中红霉素的含量

摘 要 目的：建立红霉素肠溶胶囊的含量测定方法。 方法: 采用紫外分光光度法,红霉素与氢氧化钠溶液反应生成在235 nm波长处有最大吸收峰的不饱和酮,根据不饱和酮的紫外吸收值来确定红霉素肠溶胶囊的含量。结果: 红霉素在51.18～307.08 μg·mL^-1的浓度范围内线性关系良好（r=0.999 9）,平均回收率为99.9%,RSD为1.2%（n=6）。结论:该方法简便、准确、灵敏度高、重复性好,可用于红霉素肠溶胶囊的含量测定。     

HPLC法测定琥乙红霉素口服制剂中红霉素残留量

目的建立琥乙红霉素口服制剂中红霉素残留量的检测方法.方法采用HamilT＆NRP-1 L21(250mm×4.6mm)色譜柱,柱温60℃,磷酸盐缓冲液(0.067mol·L-1,pH9.0)-乙晴-叔丁醇-水(4535128)为流动相,流速0.8ml·min-1,检测波长215nm,进样量100μL.结果红霉素在300u·ml-1～3000u·ml-1范围内呈良好线性关系(r=0.9995),平均回收率为103.7%,RSD为1.1%,最低检测限为15u.结论该法专属性强,灵敏度高,重现性较好,可作为琥乙红霉素口服制剂中红霉素残留量的测定方法.     

高效液相色谱法测定红霉素眼膏的含量

目的 建立高效液相色谱法测定红霉素眼膏的含量.方法 采用十八烷基硅烷键合硅胶(5um)为分析柱.流动相:0.1mol/L磷酸二氢铵溶液(三乙胺调节pH6.5)-乙腈(70∶30);流速:1.0ml/min;检测波长210nm.进样量20ul.结果 在进样量2.5～80.0 ug的范围内,进样量与峰面积线性关系良好(r=0.9999),重复进样RSD=0.31%.结论 该方法简便快速,重现性好,可作为红霉素眼膏的含量测定方法.     

高速逆流色谱法分离制备红霉素中的红霉素A及红霉素B

应用高速逆流色谱法,以正己烷-乙酸乙酯-甲醇-水(5:5:5:5)为两相溶剂系统,从红霉素中分离制得红霉素A和红霉素B,纯度分别为98.18%和99.05%。     

Liver Enzyme Activities after Multiple Administration of Nifedipine in Mice

Abstract: The effect of multiple nifedipine administration on hexobarbital sleeping time, liver monooxygenase and synthetase activities, lipid peroxidation and microsomal membrane fluidity were studied in male albino mice. The drug was administered orally at a dose of 25 mg/kg daily for 14 and 21 days. Nifedipine caused enzyme induction, demonstrated by shortened hexobarbital sleeping time, enhanced ethylmorphine N-demethylase, aniline 4-hydroxylase, ethoxycoumarine O-deethylase, UDP-glucuronyl transferase, glutathione S-transferase and NADPH-cytochrome c reductase activities and increased content of cytochrome P450 and cytochrome b₅. This effect persisted until the 7th day after the last dose of nifedipine. There were no changes in lipid peroxidation and fluidity of the microsomal membranes after 14-day nifedipine administration. The increased cytochrome P450 content and drug metabolizing enzyme activities could be not associated with changes in these liver microsomal membrane properties.     

Verapamil and Nifedipine Inhibition of Contractions Induced by Potassium and Noradrenaline in Human Mesenteric Arteries and Veins

Abstract Ring preparations of human mesenteric arteries and veins were contracted by noradrenaline (1.8×10^-5M) or potassium (127mM). Isometric tension was recorded. In the arterial preparations, the maximum response to noradrenaline was 97±8% (mean±S.E.M.) of that to potassium. In the veins, the corresponding figure was 38±4%. The calcium antagonists verapamil (2.2±10^-7-2.2± 10^-5M) and nifedipine (2.9×10^-8-2.9×10^-6M) relaxed both arteries and veins contracted by noradrenaline or potassium, and reduced the responses to these agents when added 15 min. before stimulation. The time course of relaxation of potassium contracted preparations, induced by verapamil and nifedipine, was more rapid and complete than that produced by a calcium-free, high potassium solution. In contrast to verapamil, nifedipine caused a more pronounced inhibition of the potassium than of the noradrenaline evoked contractions in both arteries and veins. After exposure to a calcium-free medium for 30 min., the arterial response to noradrenaline was significantly (P<0.05) greater than that to potassium. However, the reverse was found in the veins. In both types of vessel, verapamil (2.2×10^-6M) and nifedipine (2.9-10^-7M) were equi-effective in reducing the noradrenaline and potassium induced responses in calcium-free medium. The results suggest that there are differences in reactivity, not only between mesenteric arteries and veins, but also between, e.g. peripheral and mesenteric vessels. The calcium antagonists nifedipine and verapamil do not have an identical mode of action. However, both agents seem to inhibit influx of extracellular calcium, and might also have an inhibitory effect on the release of intracellular calcium.     

In Vitro Metabolism of p-Xylene by Rabbit Lung and Liver

1. Optimum conditions for metabolism in vitro of p-xylene by rabbit liver or lung microsomal enzymes have been studied. Reactions were linear with time for at least 30?min at a microsomal protein concentration of 1?mg/ml. Addition of cytosol fraction to incubation mixtures of microsomes, NADPH, and substrate increased enzyme activity but the increase was independent of amount of cytosol added (over range of 0.1 ml to 0.5 ml). The pH optimum for the lung and liver microsomal system was 7.3 and 7.8, respectively, using Hepes buffer. The apparent K_m and V_max for the liver and lung systems were determined. The NAD⁺ and NADP⁺ requirements were studied.

2. The major metabolite of p-xylene in vitro, as determined by t.l.c., of liver and lung microsomal incubation mixtures was p-toluic acid.

3. Phenobarbital pre-treatment of rabbits (multiple doses, intraperitoneal or intravenous) induced the liver microsomal xylene-metabolizing system approximately 3-fold, whereas there was no change in activity of the lung enzyme. Maximum induction of liver microsomal metabolism after a single intraperitoneal dose of phenobarbital (100?mg/kg) was reached in 2–3 days and declined slowly thereafter; during this same period lung xylene-metabolizing activity remained unchanged or increased only slightly. Chlorpromazine pre-treatment, intraperitoneal (but not intravenous), of rabbits stimulated hepatic microsomal xylene-metabolizing activity. Administration of 1,2,3,4-dibenzanthracene or 3-methylcholanthrene to rabbits resuited in decreased xylene metabolism in vitro by liver and lung microsomes.     

Inhibition of Hepatic Microsomal Drug Metabolism by Atracurium Administration in the Rat

The muscle relaxant atracurium is known to undergo extrahepatic degradation via Hofmann elimination and ester hydrolysis. The purpose of the present study was to evaluate the effects of atracurium on hepatic P450-dependent enzyme activities. Thirty-two male Sprague-Dawley rats were anaesthetized, mechanically ventilated, and randomly allocated to one of four study groups: group 1 received saline, group 2 atracurium, group 3 vecuronium, and group 4 pancuronium intravenously for a period of 3 hr. Equipotent doses of the muscle relaxants were applied; the doses had been obtained in a pilot study using evoked electromyography. At the end of the study period, the livers were removed and analyzed. All three muscle relaxants may lead to inhibition of hepatic drug metabolism. Atracurium influences hepatic P450, although it is predominantly degraded in extrahepatic tissues. Further studies are needed to evaluate the contribution of the major metabolite laudanosine to this inhibitory action.     

Metabolism of Morphine in the Perfused Rat Liver

Abstract Morphine concentrations in the recirculating plasma of a perfused rat liver preparation declined in a monoexponential manner with a half–life of 5.3 ± 0.4 min. The mean hepatic clearance was calculated to 13.1 ± 1.0 ml–min.^–1, and using an average blood flow of 17.3 ml min.^–1 this corresponds to an extraction ratio of 0.76 ± 0.02. In experiments with steady state concentration of morphine almost identical results were obtained. Measurements of different morphine concentrations in the in– and outflow of plasma of the liver yielded a mean clearance of 13.3 ± 0.7 ml–min.^–1 and a mean extraction ratio of 0.77 ± 0.03, indicating a constant clearance at different concentrations. The clearance of morphine in the perfused liver experiments was in close agreement with an in vivo calculated hepatic clearance of 75 % of the total body clearance. It is concluded that the blood flow to the liver can be an important factor in determining availability of orally administered morphine, and that the high hepatic extraction of this drug can explain the low effectiveness of this mode of administration.     

大鼠原位肝移植与异位阶段性小肠移植细胞凋亡的差异

目的：将具有免疫特穗性质的移植肝脏与免疫排斥最强度的移植小肠相比较,探讨肝脏移植的特点,方法：对接受肝移植和小肠移植大鼠移植物内凋亡细胞进行观察。结果：移植肝脏内以间质细胞凋亡为主,移植小肠内以实验质细胞凋亡为主,结论：小肠腺上皮调亡在小肠排斥反应中起重要作用。移植肝脏通过浸润细胞凋亡得到保护。     

Interaction between Erythromycin and Nitrazepam in Healthy Volunteers

Abstract: Interaction between erythromycin, a strong inhibitor of CYP3A4, and nitrazepam, a long-acting benzodiazepine, was investigated in a double-blind and randomized cross-over study of two phases. Ten healthy volunteers received erythromycin (500 mgx3) orally or placebo for 6 days. On the fourth day they were given a challenge dose of 5 mg nitrazepam. Plasma samples were collected and psychomotor effects were measured during 42 hr after intake of nitrazepam. There was a statistically significant pharmacokinetic interaction between erythromycin and nitrazepam. Erythromycin increased the area under the nitrazepam concentration-time curve by 25% (P<0.05) and the peak concentration by 30% (P<0.05). The concentration peak time of nitrazepam was shortened by over 50% (P<0.05). The elimination half-lives did not change. Accordingly, as far as the metabolism of nitrazepam is concerned, erythromycin does not cause any major changes in the metabolism of nitrazepam. In psychomotor performance only minor differences were seen. It is concluded that the interaction between erythromycin and nitrazepam is of little clinical significance.     

Metabolism of Zearalenone in Rat Liver

Abstract The metabolism of zearalenone in rat liver has been investigated. The studies were performed mainly with liver homogenate, though isolated microsomes and hepatocytes have also been used. Zearalenone was metabolized along two principal pathways, conjugation with glucuronic acid, which was the main route and reduction to an isomer of zearalenol. In no case, however, could all zearalenone metabolized be accounted for as conjugated zearalenone and free and conjugated zearalenol. Therefore another, so far unknown metabolite cannot be excluded. Reduction to zearalenol could be increased three times by the addition of NADH (or NADPH) and is probably catalyzed by a hydroxysteroid dehydrogenase. Some 25–50 per cent of the zearalenol could be conjugated, depending on the incubation conditions. The capacity of hepatocytes to eliminate zearalenone was estimated to be about 100 μg per gram of liver in one hour. With a liver homogenate the highest value obtained was 82 μg.