Effect of PCB (polychlorobiphenyls) on on L-ascorbic acid, pyridoxal phosphate and riboflavin contents in various organs and on hepatic metabolism of L-ascorbic acid in the rat.

Effects of continuous oral administration of PCB (polychlorobiphenyls, 10-100 mg/kg/day, 4 weeks) on tissue levels of L-ascorbic acid (vitamin C), pyridoxal phosphate and riboflavin (vitamin B2) in various organs and on hepatic metabolism of L-ascorbic acid were examined in male Wistar rats weighing 150-250 g. Riboflavin contents in the liver, kidney, brain, heart and testis were not altered by PCB treatments, whereas the hepatic level of pyridoxal phosphate, a biologically active form of vitamin B6, was significantly reduced by PCB administration. Under the same experimental conditions, L-ascorbic acid contents in the liver, kidney, lung and testis showed a significant increase. Histochemical studied revealed that in the adrenal gland, increase of L-ascorbic acid was localized in the fasciculate and reticular zones of cortex, respectively. It was found that increase of L-ascorbic acid in the liver is caused predominantly by activation of biosynthesis at the steps of galactose to D-glucuronic acid and is not due to changes in the catabolic processes of L-ascorbic acid per se. Possible significance of these changes in tissue levels and/or metabolism of vitamins in the occurrence of PCB intoxication is briefly discussed.     

The effect of route of administration on the cimetidine-theophylline drug interaction

The effect of route of cimetidine administration on cimetidine-mediated inhibition of theophylline oxidation was examined in healthy individuals. Based on the evidence that cimetidine-mediated inhibition of drug oxidation is competitive and, therefore, dependent on cimetidine concentration in the liver, oral cimetidine was tested to determine whether it would cause greater inhibition of drug oxidation than intravenous (IV) cimetidine. Both oral and IV cimetidine decreased theophylline clearance to the same extent. However, when clearance was corrected for cimetidine AUC, oral cimetidine resulted in a greater inhibition than IV cimetidine. Thus, the potential for increased inhibitory effect of oral cimetidine was balanced by decreased absorption after oral administration. Degree of inhibition (absolute change in theophylline clearance) and percent of inhibition after cimetidine correlated with the basal theophylline clearance. Individuals with higher basal theophylline clearances had greater degree and percent of inhibition than individuals with lower basal theophylline clearances.     

Beneficial effects of vitamin C and vitamin E on reserpine-induced oral dyskinesia in rats: critical role of striatal catalase activity

Oral dyskinesias are implicated in a series of neuropathologies and have been associated to an increase in oxidative stress. Several antioxidants, including vitamin E, decrease reserpine-induced oral dyskinesia (OD) in rodents and we have described a protective role of striatal catalase against the development of OD. The aim of this study was to verify the effects of vitamin C alone or in combination with vitamin E on reserpine-induced OD as well as to determine a possible role of catalase in the antidyskinetic property of these vitamins. Different doses of vitamin C attenuated reserpine-induced increase in OD. A similar treatment with an effective dose of vitamin C concomitant to an effective dose of vitamin E potentiated the antidyskinetic effect of both vitamins when administered alone. The administration of these vitamins alone produced an increase in striatal catalase activity that likewise was potentiated by their combined administration. In addition, the antidyskinetic property of vitamin E and vitamin C was abolished by a concomitant treatment with the catalase inhibitor aminotriazole. These results indicate a beneficial effect of these vitamins and reinforce the critical role of striatal catalase against the development of oral dyskinesias.     

Distribution and excretion of methamphetamine and its metabolites in rats. II. Time-course of concentration in blood and distribution after multiple oral administration

The time-course of total blood radioactivity after oral administration of 3H-methamphetamine, following multiple oral administration of non-radioactive methamphetamine for 7 and 14 days to rats, was examined to elucidate the effects of multiple administration on enterohepatic circulation. Whole-body autoradiographs of rats after oral administration of 14C-methamphetamine showed high levels of radioactivity in contents of stomach and small intestine, bladder urine, liver, and various glands. Distribution of methamphetamine and the major metabolite in tissues during multiple dosing was investigated; accumulation occurred in brain, liver, testis and fat. Multiple oral administration of methamphetamine to rats slightly induced enzyme activities of N-demethylation and aromatic hydroxylation of methamphetamine in rat-liver 9000 g supernatant.     

人参茎叶皂甙(SSLG)对实验性肝损伤的影响

SSLG可抑制CCl₄和硫代乙酰胺中毒小鼠SGPT的升高和肝中P-450、RNA及糖元含量的降低。此外,SSLG还能降低中毒大鼠肝中脂肪和羟脯氨酸的含量。对于小鼠的免疫性肝损伤,SSLG仅能使血中LDH-5含量降低,而对血清免疫复合物含量及组织学改变均无影响。SSLG还可诱导正常或中毒小鼠肝脏P-450含量增加及缩短小鼠的戊巴比妥钠睡眠时间,并能促进肝脏排泄BSP的功能。上述结果表明,SSLG对实验性肝损伤具有一定的保护作用。     

The mode for the manifestation of the inhibitory effects of ifenprodil tartrate on platelet aggregation in vivo and ex vivo

The mode for the manifestation of the inhibitory effect of ifenprodil tartrate on platelet aggregation in vivo and ex vivo was studied in mice and men, respectively. The ifenprodil level in plasma reached the maximum in 20 min after oral administration of 30 mg ifenprodil tartrate/kg in mice, and it decreased over a 3 hr period after the administration. On the other hand, the maximal inhibitory effect was observed 60 min after the administration. Thus ifenprodil tartrate manifested its inhibitory effect on platelet aggregation only after the maximum plasma concentration of ifenprodil was reached. The same phenomenon was observed with the inhibitory effects of ifenprodil tartrate on platelet aggregation ex vivo in man. To clarify the reason for the delay in the manifestation of the inhibitory effects of ifenprodil, the ifenprodil contents in mouse platelets after the oral administration of the drug was measured. The pattern of change in the ifenprodil contents in platelets was found to resemble closely the pattern of the change in its inhibitory effects, suggesting that the manifestation of the inhibitory effects on platelet aggregation by oral administration of ifenprodil tartrate was directly related to the ifenprodil contents in platelets rather than the ifenprodil level in plasma.     

Role of antioxidant vitamins administration on the oxidative stress

The health-promoting effects of antioxidant vitamins C and E supplementation are unclear. This study investigated the effects of vitamins C and E on the activities of reactive oxygen species (ROS)-scavenging enzymes and protein and lipid peroxidation statuses under resting and exercise-induced conditions. Thirteen healthy, previously untrained males (age 20–21 years) participated in this study. Seven subjects performed physical exercise using a cycle ergometer, and six performed a 6-min walk test (6MWT) prior to vitamin administration and after 1-week oral administration of vitamin C (1000 mg/day) and vitamin E (300 IU/day). Venous blood samples were collected before and after exercise. Plasma vitamin C concentration, superoxide dismutase (SOD) activity, glutathione peroxidase (GPx) activity, and protein carbonyl and thiobarbituric acid-reactive substance (TBARS) contents were measured. Antioxidant supplementation increased vitamin C concentration by 34% (p<0.05), decreased SOD activity by 17% (p<0.05), increased GPx activity by 13% (p<0.05), and increased the GPx/SOD activity ratio by 37% (p<0.05). Protein carbonyl and TBARS contents were unaffected. Antioxidant vitamins effectively increase the plasma GPx/SOD activity ratio, but fail to reduce protein carbonyl levels induced by exercise.     

葡萄内酯在小鼠体内的组织分布

目的:考察灌胃给药后葡萄内酯在小鼠体内各个组织中的分布情况。方法:给药后,于不同时间点取心、肝、脾、肺、肾、脑、胃、肠、肌肉、脂肪10个组织,制成组织匀浆,用乙酸乙酯萃取富集,氮吹处理后甲醇定容,采用高效液相色谱法测定并计算各个组织中葡萄内酯的浓度。结果:给药后30 min各组织中药物浓度由高到低依次为:胃>肠>肝脏>脂肪>肾>心脏>肌肉>肺>脾>脑;给药后120 min心、肝、脾、肾、脑等组织中出现分布高峰;480 min后依次消除。结论:葡萄内酯能被迅速吸收并广泛分布到各个组织,但吸收消化的过程比较持久,能透过血脑屏障,在靶器官中的作用时间>8 h。     

Distribution and excretion of methamphetamine and its metabolites in rats II. Time-course of concentration in blood and distribution after multiple oral administration

1. The time-course of total blood radioactivity after oral administration of ³H-methamphetamine, following multiple oral administration of non-radioactive methamphetamine for 7 and 14 days to rats, was examined to elucidate the effects of multiple administration on enterohepatic circulation.

2. Whole-body auto radiographs of rats after oral administration of ¹⁴C-methamphetamine showed high levels of radioactivity in contents of stomach and small intestine, bladder urine, liver, and various glands.

3. Distribution of methamphetamine and the major metabolite in tissues during multiple dosing was investigated; accumulation occurred in brain, liver, testis and fat.

4. Multiple oral administration of methamphetamine to rats slightly induced enzyme activities of N-demethylation and aromatic hydroxylation of methamphetamine in rat-liver 9000 g supernatant.     

黄芪与绿豆对砒石染毒大鼠的影响

目的 :为探讨中药黄芪与绿豆对砒石染毒大鼠毒副作用的拮抗情况及其保护作用与金属硫蛋白(MT)的关系。方法 :用黄芪、绿豆及阳性对照药物氯化镉 (CdCl2 )相比较 ,运用镉饱和法及RT PCR测定肝细胞MT的量及mRNA的表达 ,并通过检测丙氨酸氨基转移酶 (ALT)、血尿素氮 (BUN)、血清肌酐(SCR)观察其对砒石引起的肾脏、肝脏的保护作用。结果 :测的的MT的量与其mRNA表达的量具有一致性 ,砒石、黄芪、绿豆均能诱导MT的合成 ,单纯砒石诱导MT的量很少 ,增加黄芪、绿豆后表达量明显增加 ,黄芪与绿豆共同作用增加更明显 (P <0 .0 5 )。结论 :黄芪与绿豆对砒石染毒大鼠金属硫蛋白均有影响 ,对砒石毒性有一定的拮抗作用。     

Oral absorption and selective tissue localization of 4'-(9-acridinylamino)-methanesulfon-m-anisidide.

The disposition of 4'-(9-acridinylamino)-methanesulfon-m-anisidide (AMSA), a new antitumor agent presently undergoing clinical evaluation, was studied in mice and rats following oral administration and compared to that observed following intravenous administration. The metabolic fate of AMSA was the same with either intravenous or oral administration; however, the tissue distribution of AMSA differed significantly between the two routes of administration. Following absorption from the GI tract, AMSA was rapidly cleared from plasma by the liver and excreted in the bile as metabolites. Concentrations of AMSA in the liver were relatively high after oral administration and were sufficient to exert a cytotoxic effect on L1210 cells implanted at the site. The results indicate the use of AMSA orally to attain selective localization in the liver with decreased systemic exposure, which may prove useful against tumor metastases to the liver or primary hepatocellular carcinoma.     

Histopathological effects of garlic on liver and lung of rats

The comparative toxic effects of oral and intraperitoneal administration of garlic extracts on lung and liver tissue of rats were studied. Administration of low doses of garlic (50 mg/kg) to rats either orally or intraperitoneally had little effect on lung and liver tissues as compared to control animals. In contrast, administration of high doses of garlic (500 mg/kg) resulted in profound changes in lung and liver tissues of rats. Intraperitoneal administration of the high dose of garlic was more damaging to lung and liver tissue of rats than oral administration.     

Beneficial effects of cordycepin on metabolic profiles of liver and plasma from hyperlipidemic hamsters

In this study, (1)H NMR-based metabonomics was applied to evaluate the beneficial effects of cordycepin (3'-deoxyadenosine), a natural monomer compound, on endogenous metabolic profiles of liver and plasma from hyperlipidemic Syrian golden hamsters. Hyperlipidemia was successfully established in hamsters fed by a high-fat diet for 2 weeks. The hyperlipidemic hamsters were treated with an oral administration of simvastatin (2?mg?kg(-?1)) or cordycepin (140?mg?kg(-?1)) for consecutive 4 weeks. The metabolic profiles of plasma and intact liver tissues were established using (1)H NMR spectroscopy. The results showed higher contents of lipids (triglyceride and cholesterol), lactate, acetate, alanine, glutamine together with lower contents of choline-containing compounds (e.g. phosphocholine, phosphatidylcholine, and glycerophosphocholine), glucose, and glycogen in plasma and liver samples from hyperlipidemic hamsters than those in controls. Cordycepin afforded a little lipid-regulating activity on plasma but more beneficial effects on liver, implicating that cordycepin might have a protective effect on liver under fatty liver condition.     

Effect of tin on calcium content in the bile of rats

The effect of tin on bile calcium content has been investigated in rats given stannous chloride orally. The bile calcium content was linearly increased by a single oral administration of tin (10, 30, or 50 mg of Sn/kg). The administration of tin also caused a significant increase in the bile calcium content of both fasted rats and thyroparathyroidectomized rats. Meanwhile, the administration of tin did not elevate the calcium concentration in the liver. These results indicate that the augmentation of the bile calcium content after tin administration does not result from calcium accumulation in the liver. Moreover, the bile calcium content was markedly increased by the oral administration of tin (30 mg/kg every 12 hr) for 3 days, while the serum calcium concentration was reduced significantly. The present results suggest that the hypocalcemic effect of tin is partly caused by an increase in the calcium content of the bile.     

探究黑胡椒粉对SD大鼠肝脏七种主要P450酶亚型的影响

目的进行大鼠体内外实验探究黑胡椒粉对肝脏七种主要P450酶亚型的影响。方法采用体外探针底物孵育法结合LC-MS/MS技术测定黑胡椒粉乙醇提取物与大鼠肝微粒体共孵育各时间点七种酶亚型的酶活力;采用Cocktail探针法结合LC-MS/MS技术测定体内连续灌胃黑胡椒粉一、二和三天大鼠肝脏七种酶亚型的酶活力。结果与对照组相比,黑胡椒粉乙醇提取物在体外实验中对大鼠CYP2D2、CYP3A、CYP2C11、CYP2E1和CYP1A2具有抑制作用;与空白组相比,灌胃黑胡椒粉一天对大鼠CYP2A5、CYP2D2和CYP1A2具有明显的诱导作用,且诱导作用在连续灌胃二和三天随之减弱。结论黑胡椒粉对大鼠肝脏P450酶有诱导作用,且经P450酶代谢产生的代谢产物是其诱导作用的物质基础。     

淫羊藿总黄酮对四氧嘧啶糖尿病小鼠降糖作用的研究

目的 探讨淫羊藿总黄酮对四氧嘧啶所致糖尿病小鼠的降糖作用.方法 以200 mg·kg-1的剂量给小鼠腹腔注射四氧嘧啶造成糖尿病模型,按照50 mg·kg-1、100 mg·kg-1的剂量连续灌胃14 d后,取血测空腹血糖、SOD、MDA,并测定肝糖原和肌糖原含量,同时进行糖耐量实验.结果 淫羊藿总黄酮能够降低糖尿病小鼠...     

Gastrointestinal,liver, and lung extraction ratio of acetaminophen in the rat after high dose administration

The pharmacokinetics of acetaminophen was examined in rats after administration of a single dose of 200 mg kg^?1 by the intra-arterial, intravenous, portal vein, and oral routes. Levels of acetaminophen and its two major metabolites, acetaminophen-glucuronide and acetaminophen-sulfate, were quantitated in plasma at various time points for about 5 h after drug administration. The relative contribution of the gastrointestinal tract, liver, and lung to the oral extraction ratio (first-pass effect after oral absorption) was determined. A mean oral extraction ratio of 0·49 was obtained. The mean relative extraction ratio of the gastrointestinal tract, liver, and lung were 0·52, 0·07, and 0, respectively, indicating a major contribution due to the gastrointestinal tract. This is in contrast to earlier studies which have indicated negligible contribution by the gastrointestinal tract to the oral first-pass effect when lower doses were utilized. These results suggest that the relative contribution of the gastrointestinal tract and liver to the oral first-pass effect of acetaminophen may be dose-dependent.     

Investigations on the basis for the differential toxicity of hexachlorocyclopentadiene administered to rats by various routes

The differential disposition of hexachlorocyclopentadiene (HCCP) following oral administration, as contrasted to inhalation or intravenous administration, may account for its lower toxicity by this route. Following an intravenous dose of [14C]HCCP to rats at 0.59 mg/kg, 39.0% of the radioactivity remained in the tissues at 72 h; after inhalation of vapors of [14C]HCCP (1.3-1.8 mg/kg), this amount was 11.5%. After oral doses of 4.1 or 61 mg/kg, however, the amount was only 2.4%. No detectable amount of intact HCCP was present in the lungs or kidneys of rats exposed to the chemical by inhalation, and only about 1% was converted to CO2, regardless of the route of administration. The chemical reactivity of HCCP with biological materials was evident in in vitro experiments, in which HCCP became bound to components of whole blood, plasma, liver homogenates, fecal homogenates, and intestinal contents. Thus, the lower toxicity of oral doses of HCCP may be related to its reaction with intestinal contents and its lack of absorption into tissues, in substantial amounts, as the intact, reactive form.     

Possibility of Partial Absorption of Nicardipine by Routes Other Than the Hepato-portal System After Oral Administration in Rats

The systemic availability of nicardipine after different routes of administration has been examined in rats, with particular attention to differentiating oral absorption from intestinal and hepatic metabolism. The quantities of nicardipine and its metabolite were determined by capillary column gas chromatography. A linear relationship was shown between the hepatic first-pass effect and dose after hepato-portal administration of nicardipine; the hepatic first-pass effect was calculated to be approximately 80%. However, the availability after oral and rectal administration was found to be more than twice that observed after hepato-portal administration. Partial avoidance of the hepatic first-pass effect after oral and rectal administration are estimated to be 37.3% and 35.2%, respectively, assuming that all absorbed molecules pass through the liver. These findings suggest that the absorption of nicardipine after oral administration also occurs by routes other than the hepato-portal system.     

The role of the gut flora in the reduction of sulphinpyrazone in the rat

Sulphinpyrazone underwent both reduction to a sulphide and oxidation to a sulphone after parenteral administration to normal Wistar rats. Oral administration was associated with a bioavailability of about 75% and with a 3-fold greater formation of the sulphide. However, no sulphide was detected in the plasma after oral administration of sulphinpyrazone to germ-free (BD/X) rats or normal rats treated with oral antibiotics. In vitro studies showed that the major site of reduction of sulphinpyrazone was the contents of the hind gut with little activity detected in the liver or other tissues. The sulphide was oxidised in vivo to sulphinpyrazone and small amounts of sulphone, while the latter underwent only slight reduction to sulphinpyrazone, but did not give detectable levels of the sulphide. These data suggest that the gut microflora are the main site of reduction of sulphinpyrazone in the rat in vivo.