Pharmacokinetics of tacrolimus and mycophenolic acid are altered, but recover at different times during hepatic regeneration in rats.

Hepatic regeneration is very critical to the success of living donor liver transplantation, which allows a reduced size liver to grow in size to accommodate the requirements of both the donor and the recipient. The objectives of this study were to evaluate 1) the hepatic metabolism of the two immunosuppressive drugs, tacrolimus and mycophenolic acid (MPA), and 2) the pharmacokinetics of tacrolimus and mycophenolic acid at various time points after initiation of hepatic regeneration by partial hepatectomy in rats. The hepatic intrinsic clearance of tacrolimus was decreased to 70% and 51% of the control level at the 24th h and the 6th day, respectively, but returned to normal level by day 14. The total body clearance of tacrolimus was reduced transiently but recovered completely by day 18. The hepatic intrinsic clearance of MPA was decreased to 52% and 51% of that in control rats at the 24th h and the 6th day, respectively, but recovered to normal level by day 14. The total body clearance of MPA was reduced at the 24th h but recovered by day 6. The magnitude of reduction in the clearance of tacrolimus and MPA was much smaller than what was predicted from in vitro data. The elimination clearance of MPA glucuronide was also impaired during hepatic regeneration but recovered to normal level with time. In conclusion, the pharmacokinetics of tacrolimus and mycophenolic acid were altered during hepatic regeneration but recovered completely at different rates over time. Caution must be exercised in extrapolating in vitro data to in vivo conditions during hepatic regeneration.     

低水平甲基汞暴露后汞在大鼠母仔亚细胞水平的分布特征

继日本和伊拉克发生汞中毒公害病事件后,环境中汞和甲基汞对生态的破坏及对人体健康的影响受到联合国环境署(UNEP)和世界卫生组织(WHO)及社会的日益广泛关注.     

Toxic effects of carbendazim at low dose levels in male rats

Carbendazim is a systemic broad-spectrum fungicide controlling a wide range of pathogens. It is also used as a preservative in paint, papermaking and leather industry, and as a preservative of fruits. In the present study, low dose intracellular effect of carbendazim was investigated employing 5, 10, 25 and 50 mM of the compound administered to male rats intradermally. Blood and liver of each animal was collected 6 hrs later to analyze serum and tissue enzyme activities, tissue lipid peroxidation and hematological and biochemical parameters. The experimental results of low dosage carbendazim use indicated augmentation of investigated parameters. However, the higher dosage of carbendazim use resulted in renormalization of investigated parameters to control levels or to values below control, providing a U-shaped hormesis type dose-response profile. Histopathological sections revealed portal vein congestion, mononuclear cell infiltration and hydropic degeneration of the liver tissue. These results indicated that carbendazim even at low dose exhibited toxicity, affected the liver and also caused specific changes in hematological and biochemical parameters in the rat.     

Subcellular distribution and protein binding of perfluorooctanoic acid in rat liver and kidney

Perfluorooctanoic acid (PFOA) is an organic fluorochemical, and its elimination in rats is markedly sex-dependent. Liver and kidney are two primary tissues of distribution of PFOA in rats. In this study, the subcellular distribution of PFOA in male and female rat liver and kidney was examined. The results demonstrated that PFOA content in the liver cytosol of the female rat was significantly higher (49 +/- 6% of total radioactive residues, TRR) than in the male liver (26 +/- 5% TRR), whereas PFOA distribution in the heavier subcellular fractions, especially the nuclei and cell debris fraction, was marginally higher in male rat liver. In rat kidney, more than 70% of PFOA was distributed in the cytosolic fraction, with no significant difference between sexes. The degree of protein binding of PFOA in rat liver and kidney cytosol was analyzed by two different chromatographic methods. The percentage of protein-bound PFOA in the liver cytosol was found to be approximately 55% in both male and female rats. In contrast, significantly more PFOA was bound to cytosolic proteins in the kidney of male rats (42 +/- 6% TRR) than in females (17 +/- 5% TRR). Ligand blotting analysis revealed that multiple proteins from the liver cytosol, nuclei, and mitochondria fractions were capable of specific binding to PFOA.     

不同剂量阿普唑仑在大鼠体内的药动学研究

3组大鼠分别按50、20和2 mg·kg~(-1)阿普唑仑悬液,ig,体内动力学特征均符合一室开放模型.各组的吸收和消除参数无明显差异,平均值(n=18)K_a=3.3454 h~(-1).K.=0.3873 h~(-1),T_((1/2)k_(?))=0.29 h,T((1/2)K_(?))=2.61h,T_(max)=1.04 h。血药浓度与给药剂量呈正相关,3组的C_(max)(n=6)分别为4.5764、2.1793和0.2256μmol·L~(-1),r=0.6096(P<0.005);AUC分别为28.31、8.42和2.13 h·μmol·L~(-1),r=0.6854(p<0.001)、各剂量组的血药浓度和药动学参数均存在较大个体差异。     

雷公藤内酯醇在大鼠体内的组织分布

目的：建立雷公藤内酯醇的反相高效液相色谱分析方法,并对其在大鼠的组织分布进行测定。方法：用HPLC紫外检测方法测定大鼠i.v.雷公藤内酯醇后各组织中药物的含量。结果：大鼠i.v.200μg/kg的雷公藤内酯醇后药物在体内分布广泛,以肺、肝、肾中分布较高,各组织的药物含量于给药后5min最高,60min后显著下降。结论：雷公藤内酯醇在大鼠体内分布快且广泛,消除也快,且可穿越血脑屏障和血睾屏障分布到脑和睾丸中。     

Tissue distribution of N-acetylprocainamide in rats

The purpose of this study was to determine the distribution of N-acetylprocainamide (NAPA) in heart, kidney, and liver tissues of rats and their relationship to the plasma concentration after intravenous administration of the drug (100 mg/kg) to 24 Charles River rats. A specific HPLC procedure was used. The plasma and tissue concentrations of NAPA declined biexponentially in parallel, with an elimination half-life of about 1.8 hr. The equilibrium between plasma and the organs tested in this study was attained within 5 min. The tissue/plasma concentration ratio remained constant throughout the study. The tissue/plasma ratios for heart, kidney, and liver were 2.1, 7.9, and 2.4, respectively. The data indicate that: a) these organs have greater affinity to NAPA than do plasma proteins, and b) plasma concentrations may be reliable measures of the therapeutically effective concentrations at the site of action, i.e., the heart tissues.     

Comparisons of the toxicokinetic parameters in rats determined for low and high dose of gamma-chlordane

Toxicokinetic parameters of gamma-chlordane (GCD) after oral administration of various doses of radio-labelled GCD (50 micrograms/kg-10 mg/kg) were compared. Absorption of GCD were about 80% in both 0.1 and 1.0 mg/kg groups. Distributions of GCD (50 micrograms/kg and 10 mg/kg) into the liver and kidney were rapid and those into adipose tissues were relatively slow. Concentrations of GCD in adipose tissues became highest at 16 hr after administration and became about 10 times more than those in the liver. The initial concentrations of GCD calculated by two-compartment open model in high dose group (10 mg/kg) were about 200-300 times higher than those in low dose group (50 micrograms/kg). Half lives of GCD in low dose group had a tendency to be a little longer than those in high dose group. This difference seemed to be caused by the accumulation of oxychlordane in low dose group.     

不同剂量苦参碱给药后的药动学及其在唾液中的分布

目的探讨苦参碱不同剂量给药后苦参碱在大鼠体内的动态变化规律及其在唾液中的分布情况。方法大鼠静脉注射苦参碱注射液后,用反相高效液相色谱法测定苦参碱在血液、唾液中的浓度,采用药动学软件MULTI97V10进行数据处理,确定药动学参数。结果苦参碱不同剂量给药后在大鼠体内符合二室模型分布,其高、中、低剂量主要药动学参数分别如下：t1/2=2．38h,AUC=203．0g·h·L^-1,Ve=675．3mL,CL=190．6L·h^-1。t1/2=1．39h,AUC=70．7g·h·L^-1,Vc=489．4mL,CL=243．3L·h^-1;t1/2=1．66h,AUC=41．85g·h·L^-1,Ve=500．2mL,CL=208．4L·h^-1。结论通过高、中、低剂量及相应的AUC对比,可知苦参碱中、低剂量给药后在体内呈线性药动学消除过程,高剂量给药后呈非线性药动学消除过程,中、低剂量给药后,苦参碱腮腺中唾液药物浓度与血液药物浓度有一定相关性,可以考虑利用腮腺唾液代替血液进行苦参碱的药动学研究。     

Changes in lipid metabolizing enzymes of hepatic subcellular fractions from rats treated with tiadenol and clofibrate

the levels of hepatic lipid metabolizing enzymes including palmitoyl-CoA hydrolase, palmitoyl-l-carnitine hydrolase as well as some other enzymes were studied in the 100,000 g × 1 hr sediment, the corresponding supernatant and lipid-rich floating layer from rats fed tiadenol or clofibrate-containing diets (0.3 per cent $\text{w}\text{w}$). Tiadenol administration resulted in a large increase of the total activity of palmitoyl-CoA hydrolase, and of peroxisomal-CoA oxidation, while only a moderate enhancement was obtained after clofibrate feeding. the total activity of palmitoyl-l-carnitine hydrolase was increased more by tiadenol than by clofibrate. the specific activity of the two former enzymes was decreased in the particulate MLP-fraction (100,000 g × 1 hr sediment containing mitochondria, peroxisomes and microsomes) after treatment with tiadenol. The specific activity of palmitoyl-CoA hydrolase was increased more than 10-fold in the cytosolic fraction after administration of tiadenol. Tiadenol increased the specific activity of palmitoyl-l-carnitine hydrolase considerably in the cytosolic fraction, but the activity of this enzyme was little affected by clofibrate treatment. the specific activity of palmitoyl-CoA hydrolase and palmitoyl-l-carnitine hydrolase increased in the lipid-rich floating layer. Since there was also a shift in the distribution of peroxisomal palmitoyl-CoA oxidation and catalase, but not of urate oxidase after treatment with the drugs, it is suggested that the drugs induce peroxisomes with altered membrane characteristics.     

多索茶碱在大鼠的组织分布和排泄

目的:研究多索茶碱在大鼠的组织分布和排泄,为临床试验提供依据。方法:采用HPLC紫外检测方法测定大鼠灌胃口服多索茶碱后生物样品中药物的含量。结果:大鼠灌胃口服多索茶碱50mg·kg-1后的组织分布试验表明:药物主要分布在胃、肠组织,其次在肝、肾、脾、脑等组织,大部分组织的药物含量于药后0.5h最高,药后1h除胃组织外其它组织均显著下降,随后一直到2h均缓慢下降;大鼠灌胃口服多索茶碱50mg·kg-1后从(0～12h内)尿、粪和胆汁中排泄的原型药物分别占给药总量的27.12%、1.96%和1.68%。多索茶碱的人血浆蛋白结合率为92.1%。结论:多索茶碱主要分布于胃、肠、肝组织中。从粪和胆汁中排泄的原型药物很少。在尿中发现有3种代谢物。     

Tissue distribution of bitespiramycin and spiramycin in rats

AIM: To investigate the tissue distribution of bitespiramycin (BSPM) and spiramycin (SPM) in rats. METHODS: Liquid chromatographic-mass spectrometric assay was applied for the determination of three major components (isovalerylspiramycins, ISV-SPMs) of BSPM and their major active metabolites (SPMs) in rat tissues and plasma after an oral dose of bitespiramycin, as well as SPMs. RESULTS: High levels of drug concentrations were observed in most tissues, especially in the liver, stomach, intestine, spleen, lung, womb, and pancreas. BSPM persisted long time in many rat tissues such that the drug concentration in spleen was 69.4 nmol/g at 60 h post-dose and it was still above the minimum inhibitory concentration of many susceptible pathogens. At 2.5 h post-dose, the total concentrations of ISV-SPMs and SPMs achieved in tissues were from 6 to 215 times higher than the corresponding concentrations in plasma. At 2.5 h post-dose, the mean Ct/CP of BSPM appeared to be 2- or 3-fold those of SPM in most tissues. The     

溴泰君在大鼠的组织分布和排泄

目的研究溴泰君(W198)在大鼠的组织分布和排泄，为临床试验提供依据。方法用HPLC紫外检测方法测定大鼠iv W198后生物样品中的药物含量。结果大鼠iv W198 20 mg·kg^-1后组织的药物含量远高于相同时间的血清药物浓度。药物主要分布在肺，其次在肾、心、肝等组织,大部分组织的药物含量于给药后0.25 h最高，给药后2 h显著下降，至24 h均缓慢下降；大鼠iv W198 20 mg·kg^-1后从尿、粪(0-96 h)和胆汁(0-24 h)中排泄的原型药物分别占给药总量的0.150%，2.1%和0.063%。结论W198主要分布于肺组织中。从尿、粪和胆汁中排泄的原型药物很少。     

Tissue distribution and retention of cadmium in rats during postnatal development: Minimal role of hepatic metallothionein

Since liver concentration of metallothionein in 4-day-old rats is 20 times greater than that in 70-day-old adults, experiments were performed to determine whether the high concentration of metallothionein in the liver of newborn rats results in a greater distribution of cadmium to the liver and in subsequent lower concentration of cadmium in other tissues of the newborn in comparison to the adult, and if the retention of cadmium in the various tissues is affected. The concentration of cadmium in the liver of 4-day-old rats was only 30% higher than that in adult rats 2 hr after administration (1 mg/kg, iv). Even though there is no age difference in the renal concentration of metallothionein, the initial concentration of cadmium in the kidney of 4-day-old rats was half that in adult rats. However, cadmium was three to six times more concentrated, 2 hr after cadmium administration, in the spleen, bone, brain, testes, and muscle of newborn than in adult rats. Over a 19-day period, cadmium was similarly retained in the liver, kidney, and lung of newborn and adult rats, but the rate of cadmium elimination was higher from the heart and lower from the testes of newborn rats when compared to adults. These results indicate that metallothionein does not appear to play a major role in the tissue distribution and tissue retention of cadmium. The higher concentration of cadmium in some target organs, such as testes, kidneys, and lungs, of the newborn rat may have significant toxicological implications.     

Biliary and renal excretion,hepatic metabolism,and hepatic subcellular distribution of metronidazole in the rat

We studied the biliary and renal excretion, hepatic metabolism, and hepatic subcellular distribution of [¹⁴C]metronidazole in bile fistula rats. An average of 71.1 per cent of an intraduodenal or intravenous dose of [¹⁴C]metronidazole was excreted in 24 hr, 23.9 per cent in bile and 47.6 per cent in urine. Renal pedicle ligation caused a 150 per cent increase in biliary excretion of label, whereas phenobarbital pretreatment had no effect. The majority of label in bile and urine was associated with a polar derivative, tentatively identified by thin-layer chromatography and enzymatic hydrolysis as the monoglucuronide conjugate of metronidazole. After intraduodenal administration of purified conjugated [¹⁴C]metronidazole to rats with ligated renal pedicles, only a small amount of label (12.6 per cent of dose in 24 hr) appeared in bile. Growth inhibition studies showed the glucuronide conjugate to be devoid of antimicrobial activity against a metronidazole-sensitive organism, Tritrichomonas foetus. Uptake studies indicated that these organisms were incapable of concentrating conjugated metronidazole. Fractionation of rat liver homogenates by differential centrifugation after intravenous [¹⁴C]metronidazole showed that 90 per cent of label present in liver was in the non-particulate fraction. Our results in rats indicate that metronidazole undergoes an enterohepatic circulation and that the liver plays a major role in the metabolism and excretion of this compound.     

Tissue distribution of terbinafine in rats.

Terbinafine is an allylamine antifungal agent that is highly lipophilic and keratophilic. The aim of this study was to investigate terbinafine distribution in peripheral and visceral tissues after intravenous administration to rats. Terbinafine, 6 mg/kg, was administered to 33 male Sprague-Dawley rats via a jugular vein cannula over 30 s. Groups of 3 rats were sacrificed at each of 11 time points (up to 24 h), and plasma and tissues were dissected, sampled, and analyzed by high-performance liquid chromatography. Terbinafine plasma concentrations declined in a triexponential fashion, with an estimated elimination half-life of 10 h. The estimated clearance of terbinafine in rats was 2 L/h/kg and the volume of distribution at steady state was 6 L/kg. The tissue-to-plasma partition coefficient (K(p)) of terbinafine for different tissues was calculated using the ratio of the area under the curve of concentration-time for tissues (AUC(tissue)) to that for plasma (AUC(plasma)), by parametric and semiparametric approaches. There was good agreement between K(p) estimates determined by different approaches. The preferential distribution of terbinafine to adipose and skin (K(p) = 49 and 45, respectively) was consistent with the lipophilicity of the drug. Uptake of terbinafine into brain (K(p) = 1.3) and muscle (K(p) = 1.0) was significantly lower. In conclusion, terbinafine displays extensive uptake to peripheral tissues, which contributes to the long elimination half-life of this drug.     

Tissue distribution of alpha-tocopherol in nephrotic rats

1. Reactive oxygen species are involved in the pathogenesis of puromycin aminonucleoside (PAN) nephrosis and alpha-tocopherol is one of the major anti-oxidants in the body. 2. In the present study, we measured the levels of alpha-tocopherol by high-performance liquid chromatography in the plasma and in nine tissues of control and nephrotic rats obtained 10 days after either 0.9% saline solution or PAN injection, respectively. 3. In nephrotic rats, alpha-tocopherol levels increased four-fold in plasma; however, the molar ratio of alpha-tocopherol/ cholesterol remained unchanged, suggesting that the increase in alpha-tocopherol content was attributable to an increase in plasma lipid concentration. 4. In nephrotic rats, the alpha-tocopherol/cholesterol ratio increased 1.33-fold in adrenal glands and 1.34-fold in the testis, but remained unchanged in heart, spleen, liver, kidney lung, brain and muscle. 5. These data suggest that, in PAN nephrotic rats, there are alterations in the distribution of alpha-tocopherol and there is no deficiency of alpha-tocopherol in plasma or tissues.     

Biochemical effects in brain of low doses of haloperidol are qualitatively similar to those of high doses.

Typical and atypical antipsychotic drugs (APD) show differential effects in brain on both dopamine output and activation of Fos-like immunoreactivity (FLI) in dopamine nerve terminal regions. Typical APD increase dopamine output preferentially in the core and atypical APD increase dopamine output preferentially in the shell of the nucleus accumbens (NAC). Whereas both typical and atypical APD increase FLI in NAC, typicals cause FLI activation in the striatum and atypicals cause FLI activation in the prefrontal cortex. Clinically, low doses of haloperidol cause less side-effects than higher doses, and low-dose haloperidol has been suggested as a cost-effective alternative to atypical APD. Here, in vivo voltammetry in anaesthetised, pargyline-pretreated rats was used to measure dopamine output in the two subdivisions of the NAC and, in addition, immunohistochemistry was used to assess FLI activation in dopamine target areas, following acute haloperidol administration. Haloperidol, 0.001 and 0.01 mg/kg i.v., caused a significantly higher dopamine output in the core than in the shell of the NAC. Moreover, haloperidol 0.05 and 0.5, but not 0.005, mg/kg s.c. increased FLI in the NAC and the striatum, but not in the medial prefrontal cortex. Thus, even extremely low doses of haloperidol generate, in principle, the same biochemical effects in brain as higher doses, and these effects remain different from those of atypical APD. These biological data indicate that clinical differences between haloperidol and atypicals are qualitative rather than dose-dependent. Consequently, our results do not support the use of low-dose haloperidol as replacement for atypical APD in the treatment of schizophrenia.