scholarly journals Xenobiotics Inhibit Hepatic Uptake and Biliary Excretion of Taurocholate in Rat Hepatocytes

2004 ◽  
Vol 83 (2) ◽  
pp. 207-214 ◽  
Author(s):  
D. C. Kemp
Keyword(s):  
Biliary Excretion ◽  
Rat Hepatocytes ◽  
Hepatic Uptake

Role of bicarbonate in biliary excretion of diisothiocyanostilbene disulfonate

1988 ◽  
Vol 255 (6) ◽  
pp. G713-G722
Author(s):  
M. S. Anwer ◽  
K. Nolan ◽  
W. G. Hardison
Keyword(s):  
Biliary Excretion ◽  
Rat Hepatocytes ◽  
Hepatic Uptake ◽  
Disulfonic Acid ◽  
Base Line ◽  
Hepatic Transport ◽  
Isolated Rat Hepatocytes ◽  
Canalicular Membrane ◽  
Major Mechanism ◽  
Rat Livers

Hepatic transport of 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) was studied in isolated perfused rat livers and in isolated rat hepatocytes to determine if DIDS-induced decrease in biliary HCO3- excretion is due to a DIDS-HCO3- exchange and/or due to inhibition of Cl(-)-HCO3- exchange. In isolated perfused rat livers, DIDS reversibly decreased biliary HCO3- concentration and excretion. The changes in biliary HCO3- concentration were inversely related to biliary DIDS concentration. DIDS was concentrated in bile, indicating active hepatic transport. Replacement of perfusate HCO3- with equimolar dimethyloxazolidinedione (DMO) or tricine decreased biliary excretion, but not hepatic uptake, of DIDS. Biliary excretion of DIDS was also associated with a decrease in bile pH, and this decrease in pH was greater in the presence of HCO3-. HCO3-, but not DMO or tricine, stimulated DIDS efflux from preloaded hepatocytes. DIDS efflux was also temperature dependent and increased with increasing extracellular pH. Collectively, these results are consistent with the presence of a DIDS-HCO3- (OH-) exchange mechanism at the canalicular membrane. HCO3(-)-dependent Cl- uptake in hepatocytes was competitively inhibited by DIDS (Ki = 0.24 mM), confirming the presence of DIDS-inhibitable Cl(-)-HCO3- exchange. However, the ability of DIDS to decrease biliary HCO3- excretion persisted when perfusate Cl- was replaced by isethionate. Moreover, biliary HCO3- concentration returned to base line despite the presence of 2-6 mM DIDS in bile. Thus it seems unlikely that the inhibition of Cl(-)-HCO3- exchange by DIDS is a major mechanism of inhibition of HCO3- excretion. We, therefore, conclude that a DIDS-HCO3- (OH-) exchange at the canalicular membrane is the most likely explanation for the observed decrease in biliary HCO3- excretion.

scholarly journals Tacrine Sinusoidal Uptake and Biliary Excretion in Sandwich-Cultured Primary Rat Hepatocytes

2014 ◽  
Vol 17 (3) ◽  
pp. 427 ◽  
Author(s):  
Amal Kaddoumi ◽  
Loqman A. Mohamed
Keyword(s):  
Biliary Excretion ◽  
Rat Hepatocytes ◽  
Hepatic Uptake ◽  
Hepatic Transport ◽  
Glycoprotein P ◽  
Hepatic Disposition ◽  
Primary Rat Hepatocytes ◽  
Fold Reduction ◽  
Kinetics Of

PURPOSE. The knowledge of hepatic disposition kinetics of tacrine, a first cholinesterase inhibitor was approved by FDA for the treatment of Alzheimer’s disease (AD), would help to understand its hepatotoxicity, its therapeutic effect, and improve the management of patients with AD. The current study aims to characterize tacrine hepatic transport kinetics and study the role of organic cation transporters (OCTs), P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP2) in tacrine sinusoidal uptake and biliary excretion. METHODS. Modulation of tacrine hepatic uptake and efflux, biliary excretion index (BEI%), were performed in sandwich-cultured primary rat hepatocytes (SCHs) using transporters inhibitors. Conformation of the integrity of SCHs model was established by capturing images with light-contrast and fluorescence microscopy. RESULTS. Tacrine uptake in SCHs was carrier-mediated process and saturable with apparent Km of 31.5±9.6 µM and Vmax of 908±72 pmol/min/mg protein. Tetraethyl ammonium (TEA), cimetidine and verapamil significantly reduced tacrine uptake with more pronounced effect observed with verapamil which caused 3-fold reduction in tacrine uptake, indicating role for OCTs. Tacrine has a biliary excretion in SCHs with maximum BEI% value of 22.9±1.9% at 10 min of incubation. Addition of MK571 and valspodar decreased the BEI% of tacrine by 40 and 60% suggesting roles for canalicular MRP2 and P-gp, respectively. CONCLUSIONS. Our results show that in addition to metabolism, tacrine hepatic disposition is carrier-mediated process mediated by sinusoidal OCTs, and canalicular MRP2 and P-gp.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Hepatic uptake of epirubicin by isolated rat hepatocytes and its biliary excretion after intravenous infusion in rats

2014 ◽  
Vol 37 (12) ◽  
pp. 1599-1606 ◽  
Author(s):  
Dae Hwan Shin ◽  
Seong Hyeok Park ◽  
Sung Woo Jeong ◽  
Chun-Woong Park ◽  
Kun Han ◽  
...  
Keyword(s):  
Biliary Excretion ◽  
Intravenous Infusion ◽  
Rat Hepatocytes ◽  
Hepatic Uptake ◽  
Isolated Rat Hepatocytes ◽  
Isolated Rat

MULTIPLE TRANSPORT SYSTEMS MEDIATE THE HEPATIC UPTAKE AND BILIARY EXCRETION OF THE METABOLICALLY STABLE OPIOID PEPTIDE [d-PENICILLAMINE2,5]ENKEPHALIN

2004 ◽  
Vol 33 (2) ◽  
pp. 287-293 ◽  
Author(s):  
Keith A. Hoffmaster ◽  
Maciej J. Zamek-Gliszczynski ◽  
Gary M. Pollack ◽  
Kim L. R. Brouwer
Keyword(s):  
Biliary Excretion ◽  
Opioid Peptide ◽  
Hepatic Uptake ◽  
Transport Systems

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.

Hepatic uptake and biliary excretion of tetracycline in the rat

1973 ◽  
Vol 225 (5) ◽  
pp. 1240-1246 ◽  
Author(s):  
RC Lanman ◽  
S Muranishi ◽  
LS Schanker
Keyword(s):  
Biliary Excretion ◽  
Hepatic Uptake
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