Dose-Dependent Inhibition of Transporter-Mediated Hepatic Uptake and Biliary Excretion of Methotrexate by Cyclosporine A in an Isolated Perfused Rat Liver Model

2010 ◽  
Vol 99 (12) ◽  
pp. 5060-5069 ◽  
Author(s):  
Ridhi Parasrampuria ◽  
Reza Mehvar
Keyword(s):  
Rat Liver ◽  
Cyclosporine A ◽  
Biliary Excretion ◽  
Hepatic Uptake ◽  
Isolated Perfused Rat Liver ◽  
Perfused Rat Liver ◽  
Liver Model ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Dose Dependent

Effects of cyclosporine A on the hepatobiliary disposition and hepatic uptake of etoposide in an isolated perfused rat liver model

2015 ◽  
Vol 75 (5) ◽  
pp. 961-968
Author(s):  
Mina Khezrian ◽  
Behjat Sheikholeslami ◽  
Simin Dadashzadeh ◽  
Hoda Lavasani ◽  
Mohammadreza Rouini
Keyword(s):  
Rat Liver ◽  
Cyclosporine A ◽  
Hepatic Uptake ◽  
Isolated Perfused Rat Liver ◽  
Perfused Rat Liver ◽  
Liver Model ◽  
Hepatobiliary Disposition

scholarly journals Uptake, production and metabolism of cysteinyl leukotrienes in the isolated perfused rat liver. Inhibition of leukotriene uptake by cyclosporine

1989 ◽  
Vol 261 (2) ◽  
pp. 611-616 ◽  
Author(s):  
W Hagmann ◽  
S Parthé ◽  
I Kaiser
Keyword(s):  
Rat Liver ◽  
Immunosuppressive Drug ◽  
Isolated Perfused Rat Liver ◽  
Ionophore A23187 ◽  
Uptake System ◽  
Perfused Rat Liver ◽  
Beta Oxidation ◽  
Cysteinyl Leukotrienes ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition

1. The isolated perfused rat liver efficiently takes up cysteinyl leukotrienes (LTs) C4, D4, E4 and N-acetyl-LTE4 from circulation. More than 70% of these cysteinyl LTs are excreted from liver into bile within 1 h of onset of a 5 min infusion, while about 5% remain in the liver. About 20% of infused N-acetyl-LTE4 escapes hepatic first-pass extraction under our conditions. 2. Metabolites of LTC4 appearing in bile within 20 min of the onset of infusion include mainly LTD4 and N-acetyl-LTE4, but also omega-hydroxy-N-acetyl-LTE4 and omega-carboxy-N-acetyl-LTE4. Metabolites generated from omega-carboxy-N-acetyl-LTE4 by beta-oxidation from the omega-end represent the major biliary LTs secreted at later times. 3. Stimulation of the isolated perfused liver by the combined infusion of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) and the Ca2+ ionophore A23187 results in a transient increase of endogenous cysteinyl LT production, which is independent of extrahepatic cells. 4. The immunosuppressive drug cyclosporine causes a dose-dependent inhibition of hepatobiliary cysteinyl LT excretion, probably by interference with the sinusoidal uptake system for cysteinyl LTs.

Effect of Hypothermia on the Hepatic Uptake and Biliary Excretion of Vecuronium in the Isolated Perfused Rat Liver

2001 ◽  
Vol 94 (2) ◽  
pp. 270-279 ◽  
Author(s):  
Ton M. Beaufort ◽  
Johannes H. Proost ◽  
Jan-Gerard Maring ◽  
Emiel R. Scheffer ◽  
J. Mark K. H. Wierda ◽  
...  
Keyword(s):  
Rat Liver ◽  
Biliary Excretion ◽  
Excretion Rate ◽  
Hepatic Uptake ◽  
Pharmacokinetic Analysis ◽  
Isolated Perfused Rat Liver ◽  
Perfused Rat Liver ◽  
Perfusion Medium ◽  
Perfusion Experiment ◽  
Biliary Excretion Rate

Background Hypothermia prolongs the time course of action of nondepolarizing muscle relaxants. It is not known whether this prolongation is caused by a reduced rate of extrahepatic distribution or elimination, liver uptake, metabolic clearance, or biliary excretion. Therefore, the authors studied the effects of hypothermia on the net hepatic uptake, metabolism, and biliary excretion of vecuronium in isolated perfused rat liver. Methods Livers of Wistar rats were perfused with Krebs Ringer solution (1% albumin, 3.3% carbon dioxide in oxygen, pH 7.36-7.42, 38 degrees C). Each perfusion experiment (recirculatory perfusion system) was divided into three phases. In phase 1, a bolus dose of vecuronium (950 microg) was followed by a continuous infusion of vecuronium (63 microg/min) throughout the perfusion experiment. In phase 2, the temperature was reduced to 28 degrees C. In phase 3, temperature was restored. In controls, the temperature was kept constant throughout the perfusion. Concentrations of vecuronium and its metabolites were measured in perfusion medium, bile, and liver homogenate. Parameters of a multicompartmental liver model were fitted to the concentration patterns in perfusion medium and in bile. Results Hypothermia increased vecuronium concentrations in the perfusion medium from 4.0 microg/ml (range, 2.5-6.6) to 15.6 microg/ml (11.5-18.4 microg/ml; P = 0.018). Hypothermia reduced the biliary excretion rate of 3-desacetyl vecuronium from 18% (range, 6-37%) to 16% (range, 4-19%) of that of vecuronium (P = 0.018). Pharmacokinetic analysis confirmed that hypothermia reduced the rate constants of hepatic uptake and metabolism from 0.219 to 0.053 and from 0.059 to 0.030, respectively. Conclusions Hypothermia significantly and reversibly reduced the net hepatic uptake of vecuronium. Hypothermia reduced the metabolism of vecuronium and the biliary excretion rate of 3-desacetyl vecuronium.

Malaria infection impairs glucuronidation and biliary excretion by the isolated perfused rat liver

Xenobiotica ◽  
1991 ◽  
Vol 21 (12) ◽  
pp. 1571-1582 ◽  
Author(s):  
R. T. Murdoch ◽  
H. Ghabrial ◽  
G. W. Mihaly ◽  
D. J. Morgan ◽  
R. A. Smallwood
Keyword(s):  
Rat Liver ◽  
Biliary Excretion ◽  
Malaria Infection ◽  
Isolated Perfused Rat Liver ◽  
Perfused Rat Liver

Metabolism and biliary excretion of trimetrexate by the isolated perfused rat liver

1985 ◽  
Vol 29 (1) ◽  
pp. 65-71 ◽  
Author(s):  
Lorraine K. Webster ◽  
William P. Tong ◽  
John J. McCormack
Keyword(s):  
Rat Liver ◽  
Biliary Excretion ◽  
Isolated Perfused Rat Liver ◽  
Perfused Rat Liver

Efficient hepatic uptake and concentrative biliary excretion of a mercapturic acid

1998 ◽  
Vol 275 (4) ◽  
pp. G612-G619 ◽  
Author(s):  
Cheri A. Hinchman ◽  
James F. Rebbeor ◽  
Nazzareno Ballatori
Keyword(s):  
Rat Liver ◽  
Biliary Excretion ◽  
Organic Anion ◽  
Hepatic Uptake ◽  
Mercapturic Acid ◽  
Whole Body ◽  
Isolated Perfused Rat Liver ◽  
Mercapturic Acids ◽  
Anion Transporters ◽  
Subsequent Degradation

The role of the liver in the disposition of circulating mercapturic acids was examined in anesthetized rats and in the isolated perfused rat liver using S-2,4-dinitrophenyl- N-acetylcysteine (DNP-NAC) as the model compound. When DNP-NAC was infused into the jugular vein (150 or 600 nmol over 60 min) it was rapidly and nearly quantitatively excreted as DNP-NAC into bile (42–36% of the dose) and urine (48–62% of dose). Some minor metabolites were detected in bile (<4%), with the major metabolite coeluting on HPLC with the DNP conjugate of glutathione (DNP-SG). Isolated rat livers perfused single pass with 3 μM DNP-NAC removed 72 ± 9% of this mercapturic acid from perfusate. This rapid DNP-NAC uptake was unaffected by sodium omission, or byl-cysteine,l-glutamate,l-cystine, or N-acetylated amino acids, but was decreased by inhibitors of hepatic sinusoidal organic anion transporters (oatp), indicating that DNP-NAC is a substrate for these transporters. The DNP-NAC removed from perfusate was promptly excreted into bile, eliciting a dose-dependent choleresis. DNP-NAC itself constituted ∼75% of the total dose recovered in bile, reaching a concentration of 9 mM when livers were perfused in a recirculating mode with an initial DNP-NAC concentration of 250 μM. Other biliary metabolites included DNP-SG, DNP-cysteinylglycine, and DNP-cysteine. DNP-SG was likely formed by a spontaneous retro-Michael reaction between glutathione and DNP-NAC. Subsequent degradation of DNP-SG by biliary γ-glutamyltranspeptidase and dipeptidase activities accounts for the cysteinylglycine and cysteine conjugates, respectively. These findings indicate the presence of efficient hepatic mechanisms for sinusoidal uptake and biliary excretion of circulating mercapturic acids in rat liver and demonstrate that the liver plays a role in their whole body elimination.

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