scholarly journals Comparison of In Vitro-In Vivo Extrapolation of Biliary Clearance Using an Empirical Scaling Factor Versus Transport-Based Scaling Factors in Sandwich-Cultured Rat Hepatocytes

2013 ◽  
Vol 102 (8) ◽  
pp. 2837-2850 ◽  
Author(s):  
Peng Zou ◽  
Xingrong Liu ◽  
Susan Wong ◽  
Meihua Rose Feng ◽  
Bianca M. Liederer
Keyword(s):  
Factor Versus ◽  
Rat Hepatocytes ◽  
Scaling Factor ◽  
Scaling Factors ◽  
Biliary Clearance ◽  
Cultured Rat Hepatocytes ◽  
In Vivo Extrapolation

Hepatic Scaling Factors for In Vitro-In Vivo Extrapolation (IVIVE) of Metabolic Drug Clearance in Patients with Colorectal Cancer with Liver Metastasis

2021 ◽  
pp. DMD-AR-2021-000359
Author(s):  
Areti-Maria Vasilogianni ◽  
Brahim Achour ◽  
Daniel Scotcher ◽  
Sheila Annie Peters ◽  
Zubida M. Al-Majdoub ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Drug Clearance ◽  
Scaling Factors ◽  
Metabolic Drug ◽  
In Vivo Extrapolation

scholarly journals Antioxidant and Preventive Effects of Extract fromNymphaea candidaFlower onIn VitroImmunological Liver Injury of Rat Primary Hepatocyte Cultures

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Jun Zhao ◽  
Tao Liu ◽  
Long Ma ◽  
Ming Yan ◽  
Zhengyi Gu ◽  
...  
Keyword(s):  
Liver Injury ◽  
Antioxidant Capacity ◽  
Antioxidant Activities ◽  
Reducing Power ◽  
Rat Hepatocytes ◽  
Butylated Hydroxytoluene ◽  
Traditional Uighur Medicine ◽  
Cultured Rat Hepatocytes

Nymphaea candidais traditional Uighur medicine that is commonly used to treat head pains, cough, hepatitis and hypertension in Xinjiang of China. In this article, the extract ofN. candidawas measured for antioxidant activity, using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals scavenging assay and reducing power determination, and compared with those of the positive controls of butylated hydroxytoluene (BHT) and gallic acid (GA). The active extract was further purified by liquid-liquid partition to afford four fractions, of which the ethyl acetate-soluble (EA) fraction (NCE) exhibited the strongest antioxidant capacity with IC50value of 12.6 g/mL for DPPH. Thirteen phenolic compounds were isolated from this fraction, and they all showed significant antioxidant activities in DPPH model system. Furthermore, NCE showed potent antioxidant capacity with IC50value of 59.32 g/mL, 24.48 g/mL and 86.85 g/mL, for ,·OH and H2O2radicals, respectively. Moreover, NCE on BCG plus LPS-induced immunological liver injury was evaluated using primary cultured rat hepatocytes. NCE produced significant hepatoprotective effects as evidenced by decreased supernatant enzyme activities (AST—aspartate transaminase,P<  .01; ALT—alanine transferase,P<  .01) and nitric oxide (NO,P<  .01) production. These results revealed thein vitroantioxidant and hepatoprotective activities of NCE against immunological liver injury. Further investigations are necessary to verify these activitiesin vivo.

Acidosis-induced downregulation of hepatocyte mitochondrial aquaporin-8 and ureagenesis from ammonia

2015 ◽  
Vol 93 (4) ◽  
pp. 417-420 ◽  
Author(s):  
Sara M. Molinas ◽  
Leandro R. Soria ◽  
Julieta Marrone ◽  
Mauro Danielli ◽  
Laura Trumper ◽  
...  
Keyword(s):  
Protein Expression ◽  
Culture Medium ◽  
Rat Hepatocytes ◽  
In Vivo Studies ◽  
Urea Synthesis ◽  
Primary Cultured Rat Hepatocytes ◽  
Urea Content ◽  
Cultured Rat Hepatocytes

It has been proposed that, during metabolic acidosis, the liver downregulates mitochondrial ammonia detoxification via ureagenesis, a bicarbonate-consuming process. Since we previously demonstrated that hepatocyte mitochondrial aquaporin-8 channels (mtAQP8) facilitate the uptake of ammonia and its metabolism into urea, we studied whether mtAQP8 is involved in the liver adaptive response to acidosis. Primary cultured rat hepatocytes were adapted to acidosis by exposing them to culture medium at pH 7.0 for 40 h. Control cells were exposed to pH 7.4. Hepatocytes exposed to acid medium showed a decrease in mtAQP8 protein expression (–30%, p < 0.05). Ureagenesis from ammonia was assessed by incubating the cells with 15N-labeled ammonia and measuring 15N-labeled urea synthesis by nuclear magnetic resonance. Reduced ureagenesis was found in acidified hepatocytes (–31%, p < 0.05). In vivo studies in rats subjected to 7 days acidosis also showed decreased protein expression of hepatic mtAQP8 (–50%, p < 0.05) and reduced liver urea content (–35%; p < 0.05). In conclusion, our in vitro and in vivo data suggest that hepatic mtAQP8 expression is downregulated in acidosis, a mechanism that may contribute to decreased ureagenesis from ammonia in response to acidosis.

scholarly journals Induction of peroxisomal β-oxidation by a microbial catabolite of cholic acid in rat liver and cultured rat hepatocytes

1993 ◽  
Vol 295 (1) ◽  
pp. 217-220 ◽  
Author(s):  
T Nishimaki-Mogami ◽  
A Takahashi ◽  
K Toyoda ◽  
Y Hayashi
Keyword(s):  
Cholic Acid ◽  
Rat Hepatocytes ◽  
Peroxisome Proliferator ◽  
Beta Oxidation ◽  
Oxidation Activity ◽  
Cultured Rat Hepatocytes ◽  
Coa Reductase ◽  
Increased Activity

The capability of (4R)-4-(2,3,4,6,6a beta,7,8,9,9a alpha,9b beta-decahydro-6a beta-methyl-3-oxo-1H-cyclopental[f]quinolin-7 beta-yl)valeric acid (DCQVA), a catabolite of cholic acid produced by enterobacteria, to induce peroxisome proliferation in vivo and in vitro was studied. Rats given 0.3% DCQVA in the diet for 2 weeks showed marked increases in peroxisomal beta-oxidation, mitochondrial 2,4-dienoyl-CoA reductase and microsomal laurate omega-oxidation activities in the liver compared with control rats given the diet without DCQVA. Cultured rat hepatocytes treated with DCQVA for 72 h also exhibited greatly enhanced beta-oxidation activity. The increased activity was concentration-dependent and the effective concentrations were comparable with those of clofibric acid that produced the same degree of induction in the assay. The results demonstrate that DCQVA is a potent peroxisome proliferator that occurs naturally in rat intestine.

scholarly journals Novel testing strategy for prediction of rat biliary excretion of intravenously administered estradiol-17β glucuronide

2020 ◽  
Author(s):  
Annelies Noorlander ◽  
Eric Fabian ◽  
Bennard van Ravenzwaay ◽  
Ivonne M. C. M. Rietjens
Keyword(s):  
Biliary Excretion ◽  
Rat Hepatocytes ◽  
Scaling Factor ◽  
Blood Levels ◽  
Testing Strategy ◽  
Predicted Values ◽  
Definition Of ◽  
Estradiol 17Β

Abstract The aim of the present study was to develop a generic rat physiologically based kinetic (PBK) model that includes a novel testing strategy where active biliary excretion is incorporated using estradiol-17β glucuronide (E217βG) as the model substance. A major challenge was the definition of the scaling factor for the in vitro to in vivo conversion of the PBK-model parameter Vmax. In vitro values for the Vmax and Km for transport of E217βG were found in the literature in four different studies based on experiments with primary rat hepatocytes. The required scaling factor was defined based on fitting the PBK model-based predicted values to reported experimental data on E217βG blood levels and cumulative biliary E217βG excretion. This resulted in a scaling factor of 129 mg protein/g liver. With this scaling factor the PBK model predicted the in vivo data for blood and cumulative biliary E217βG levels with on average of less than 1.8-fold deviation. The study provides a proof of principle on how biliary excretion can be included in a generic PBK model using primary hepatocytes to define the kinetic parameters that describe the biliary excretion.

scholarly journals Microsomal and Cytosolic Scaling Factors in Dog and Human Kidney Cortex and Application for In Vitro-In Vivo Extrapolation of Renal Metabolic Clearance

2017 ◽  
Vol 45 (5) ◽  
pp. 556-568 ◽  
Author(s):  
Daniel Scotcher ◽  
Sarah Billington ◽  
Jay Brown ◽  
Christopher R. Jones ◽  
Colin D. A. Brown ◽  
...  
Keyword(s):  
Human Kidney ◽  
Kidney Cortex ◽  
Metabolic Clearance ◽  
Scaling Factors ◽  
In Vivo Extrapolation

scholarly journals Induction of cytochrome P-450 in cultured rat hepatocytes. The heterogeneous localization of specific isoenzymes using immunocytochemistry

1989 ◽  
Vol 262 (1) ◽  
pp. 151-158 ◽  
Author(s):  
R G Bars ◽  
A M Mitchell ◽  
C R Wolf ◽  
C R Elcombe
Keyword(s):  
Primary Cultures ◽  
Liver Microsomes ◽  
Rat Hepatocytes ◽  
Clofibric Acid ◽  
Maximal Concentration ◽  
Heterogeneous Distribution ◽  
Cultured Rat Hepatocytes ◽  
Cytochrome P 450

Primary cultures of rat hepatocytes were exposed to phenobarbitone, clofibric acid, beta-naphthoflavone, isosafrole or dexamethasone for 3 days, and the induction of several cytochrome P-450 isoenzymes was demonstrated by increased catalytic activity, by Western blotting and by immunocytochemistry. The profiles of isoenzymes induced in vitro were compared with those induced in liver microsomes of rats dosed with the same agents. Clofibric acid, an agent which has not been thoroughly investigated previously, was shown to induce both in vivo and in vitro several P-450 isoenzymes normally inducible by phenobarbitone (PB1a, PB3a and PB3b) or steroids (PB2c). Immunocytochemical studies demonstrated that the inducible isoenzymes of cytochrome P-450 are not distributed evenly throughout the hepatocyte population, and increasing concentrations of phenobarbitone or beta-naphthoflavone in the medium results in an increasing proportion of ‘induced’ cells. However, whereas maximal concentrations of beta-naphthoflavone resulted in virtually all cells containing induced levels of MC1b, a maximal concentration of phenobarbitone resulted in only 30% of the cells containing induced levels of PB3a/PB3b. These results are discussed in relation to the heterogeneous distribution and induction of cytochrome P-450 in the intact liver.

Sign in / Sign up

Export Citation Format

Share Document