| Effect of multidrug resistance modulators on the hepatobiliary disposition of doxorubicin in the isolated perfused rat liver. | |
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MedLine Citation:
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PMID: 9721873 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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P-Glycoprotein (P-gp)-mediated multidrug resistance (MDR) in cancer cells may be modulated by competitive inhibitors of P-gp. In the liver, P-gp is localized on the canalicular membrane of hepatocytes. Quinidine and GF120918 inhibit the transport of P-gp substrates, including doxorubicin. Competitive inhibition of P-gp transport may alter biliary excretion of substrates. This study was designed to examine the effects of MDR modulators on the hepatobiliary disposition of doxorubicin and to elucidate the site(s) of drug-modulator interaction using pharmacokinetic modeling techniques. Livers from male Sprague Dawley rats were isolated and perfused for 2 h at 37 degrees C with recirculating male rat blood. MDR modulator (16.8-480 microg of GF120918 or 0.3-3.0 mg of quinidine) or vehicle (buffer or DMSO, respectively) was administered as a bolus to the perfusate reservoir 5 min prior to the addition of doxorubicin (464 microg). Perfusate and bile were collected during the perfusion, the liver was homogenized after the perfusion, and samples were analyzed by high-pressure liquid chromatography for doxorubicin and the major metabolite doxorubicinol. In the presence of GF120918, the biliary excretion of doxorubicin and doxorubicinol was decreased significantly without alterations in doxorubicin perfusate concentrations or doxorubicin and doxorubicinol liver concentrations. In the presence of quinidine, the biliary excretion of doxorubicin was reduced significantly; however, doxorubicinol recovery in bile was not altered. The perfusate and liver concentrations of doxorubicin were not altered by quinidine; doxorubicinol liver concentrations were increased. A series of pharmacokinetic models were evaluated incorporating perfusate, liver, and bile compartments to describe the disposition of doxorubicin and doxorubicinol in the isolated perfused rat liver. The model that best described these data, based on goodness-of-fit criteria, included first-order rate constants for all disposition processes. On the basis of this model, the rate-limiting process for doxorubicin and doxorubicinol elimination was biliary excretion. In the presence of GF120918, rate constants associated with doxorubicin and doxorubicinol canalicular egress were decreased, and other doxorubicinol disposition pathways were increased slightly. Quinidine was associated with a decrease in doxorubicin canalicular egress, doxorubicinol formation, and other doxorubicinol pathways. Pharmacokinetic modeling of the data supported the hypothesis that decreased biliary excretion of doxorubicin in the isolated perfused rat liver, as determined by mass-balance analysis, was due to interactions at the canalicular membrane. The present study further supports the utility of pharmacokinetic modeling in identifying sites of drug interactions within the hepatobiliary system. This approach may be particularly useful in predicting the effects of perturbations in hepatic translocation processes on the hepatobiliary disposition of drugs and derived metabolites. |
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Authors:
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C L Booth; K R Brouwer; K L Brouwer |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Cancer research Volume: 58 ISSN: 0008-5472 ISO Abbreviation: Cancer Res. Publication Date: 1998 Aug |
Date Detail:
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Created Date: 1998-09-17 Completed Date: 1998-09-17 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 3641-8 Citation Subset: IM |
Affiliation:
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Division of Pharmaceutics, School of Pharmacy, University of North Carolina, Chapel Hill 27599-7360, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acridines
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pharmacology* Animals Antibiotics, Antineoplastic / pharmacokinetics* Bile / drug effects, metabolism Dimethyl Sulfoxide / pharmacology Doxorubicin / analogs & derivatives*, pharmacokinetics* Drug Carriers / metabolism Drug Resistance, Multiple Drug Resistance, Neoplasm Half-Life Isoquinolines / pharmacology* Liver / drug effects*, metabolism Male Models, Biological Quinidine / pharmacology* Rats Rats, Sprague-Dawley Tetrahydroisoquinolines* |
| Grant Support | |
ID/Acronym/Agency:
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GM41935/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Acridines; 0/Antibiotics, Antineoplastic; 0/Drug Carriers; 0/Isoquinolines; 0/Tetrahydroisoquinolines; 141434-67-5/adriamycinol; 143664-11-3/GF 120918; 23214-92-8/Doxorubicin; 56-54-2/Quinidine; 67-68-5/Dimethyl Sulfoxide |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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