Liver Fibrosis Impairs Hepatic Pharmacokinetics of Liver Transplant Drugs in the Rat Model
This study aims to investigate hepatic pharmacokinetics of the four most common drugs (metoprolol, omeprazole, spironolactone, and furosemide) given to patients undergoing liver transplantation before surgery. The investigation was carried out in CCl4-induced fibrotic perfused rat livers and the res...
Gespeichert in:
| Veröffentlicht in: | DRUG METABOLISM AND PHARMACOKINETICS 2010-01, Vol.25 (5), p.442-449 |
|---|---|
| Hauptverfasser: | , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 449 |
|---|---|
| container_issue | 5 |
| container_start_page | 442 |
| container_title | DRUG METABOLISM AND PHARMACOKINETICS |
| container_volume | 25 |
| creator | Zou, Yu-Hong Liu, Xin Khlentzos, Alexander M. Asadian, Peyman Li, Peng Thorling, Camilla A. Robertson, Thomas A. Fletcher, Linda M. Crawford, Darrell H.G. Roberts, Michael S. |
| description | This study aims to investigate hepatic pharmacokinetics of the four most common drugs (metoprolol, omeprazole, spironolactone, and furosemide) given to patients undergoing liver transplantation before surgery. The investigation was carried out in CCl4-induced fibrotic perfused rat livers and the results were compared to those in normal rat liver. Drug outflow fraction-time profiles were obtained after bolus injection into a single-pass-perfused normal or fibrotic rat liver. The pharmacokinetic parameters were estimated using previously developed barrier-limited and space-distributed models. The results showed a marked increase in the liver fibrosis index for CCl4-treated rats compared to controls (p |
| doi_str_mv | 10.2133/dmpk.DMPK-10-RG-031 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_764539676</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S1347436715300549</els_id><sourcerecordid>764539676</sourcerecordid><originalsourceid>FETCH-LOGICAL-c663t-3a7d0d7fc01ad80cbffbc0298150759f1d6d0d22b10b84bd57253170d29d66283</originalsourceid><addsrcrecordid>eNp9kMFu1TAQRS0EoqXwBUjIO1YpYzuxkwUL1NLXildRPZUNG8uxHeo2iVM7qcTfM1EKSxb22DN3rmYOIe8ZnHImxCc3TA-n59c33woGxWFXgGAvyDGrayig4fAS36JURSmkOiJvcr4HEKIq-WtyxKFWion6mPzchyef6EVoU8wh06thMiFleuknMwdLb-5MGoyND2H0-M80dnRruU1mzFNvxpmep-VXpmGk852nBzPT6-h8_5a86kyf_bvneEJ-XHy9Pbss9t93V2df9oWVUsyFMMqBU50FZlwNtu261gJvalaBqpqOOYl1zlsGbV22rlK8EkxhqnFS8lqckI-b75Ti4-LzrIeQre9xNB-XrJUsK9FIJVEpNqXFZXPynZ5SGEz6rRnolalemeqV6Zo57DQyxa4Pz_5LO3j3r-cvRBTsNgFWgzV9HHukpe_jkkZcXNvIBj-bFjvQFYBXUGHAU5Z8vRomGuCco9Pnzckjr6fgk842-NGib_J21i6G_476ByEonxk</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>764539676</pqid></control><display><type>article</type><title>Liver Fibrosis Impairs Hepatic Pharmacokinetics of Liver Transplant Drugs in the Rat Model</title><source>J-STAGE Free</source><source>MEDLINE</source><source>Alma/SFX Local Collection</source><source>Free Full-Text Journals in Chemistry</source><creator>Zou, Yu-Hong ; Liu, Xin ; Khlentzos, Alexander M. ; Asadian, Peyman ; Li, Peng ; Thorling, Camilla A. ; Robertson, Thomas A. ; Fletcher, Linda M. ; Crawford, Darrell H.G. ; Roberts, Michael S.</creator><creatorcontrib>Zou, Yu-Hong ; Liu, Xin ; Khlentzos, Alexander M. ; Asadian, Peyman ; Li, Peng ; Thorling, Camilla A. ; Robertson, Thomas A. ; Fletcher, Linda M. ; Crawford, Darrell H.G. ; Roberts, Michael S. ; School of Medicine ; Department of Gastroenterology and Hepatology and School of Medicine ; University of Queensland ; School of Pharmacy & Medical Science ; Therapeutics Research Centre ; Princess Alexandra Hospital ; University of South Australia</creatorcontrib><description>This study aims to investigate hepatic pharmacokinetics of the four most common drugs (metoprolol, omeprazole, spironolactone, and furosemide) given to patients undergoing liver transplantation before surgery. The investigation was carried out in CCl4-induced fibrotic perfused rat livers and the results were compared to those in normal rat liver. Drug outflow fraction-time profiles were obtained after bolus injection into a single-pass-perfused normal or fibrotic rat liver. The pharmacokinetic parameters were estimated using previously developed barrier-limited and space-distributed models. The results showed a marked increase in the liver fibrosis index for CCl4-treated rats compared to controls (p<0.05). The extraction ratios (E) for all drugs were significantly lower (p<0.05) in fibrotic than in normal livers and the decrease in E was consistent with the decrease in intrinsic clearance and permeability-surface area product. In addition, other than for furosemide, the mean transit times for all drugs were significantly longer (p<0.01) in the fibrotic livers than in normal livers. Pharmacokinetic model and stepwise regression analyses suggest that these differences arise from a reduction in both the transport of drugs across the basolateral membrane and their metabolic clearance and were in a manner similar to those previously found for another group of drugs.</description><identifier>ISSN: 1347-4367</identifier><identifier>EISSN: 1880-0920</identifier><identifier>DOI: 10.2133/dmpk.DMPK-10-RG-031</identifier><identifier>PMID: 20877138</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Bile Ducts, Intrahepatic - drug effects ; Bile Ducts, Intrahepatic - physiopathology ; Carbon Tetrachloride - pharmacology ; Extracellular Space - drug effects ; furosemide ; Furosemide - metabolism ; Furosemide - pharmacokinetics ; hepatic pharmacokinetics ; Liver - drug effects ; Liver - metabolism ; Liver - pathology ; Liver - physiopathology ; Liver Cirrhosis - chemically induced ; Liver Cirrhosis - metabolism ; Liver Cirrhosis - physiopathology ; liver fibrosis ; Liver Transplantation ; Male ; metoprolol ; Metoprolol - metabolism ; Metoprolol - pharmacokinetics ; Models, Biological ; omeprazole ; Omeprazole - metabolism ; Omeprazole - pharmacokinetics ; Organ Size - drug effects ; Oxygen Consumption - drug effects ; Pharmaceutical Preparations - metabolism ; Pharmacokinetics ; propranolol ; Propranolol - metabolism ; Propranolol - pharmacokinetics ; Rats ; Rats, Wistar ; spironolactone ; Spironolactone - metabolism ; Spironolactone - pharmacokinetics ; Transplantation Conditioning ; Water - metabolism</subject><ispartof>DRUG METABOLISM AND PHARMACOKINETICS, 2010-01, Vol.25 (5), p.442-449</ispartof><rights>2010 The Japanese Society for the Study of Xenobiotics</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c663t-3a7d0d7fc01ad80cbffbc0298150759f1d6d0d22b10b84bd57253170d29d66283</citedby><cites>FETCH-LOGICAL-c663t-3a7d0d7fc01ad80cbffbc0298150759f1d6d0d22b10b84bd57253170d29d66283</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20877138$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zou, Yu-Hong</creatorcontrib><creatorcontrib>Liu, Xin</creatorcontrib><creatorcontrib>Khlentzos, Alexander M.</creatorcontrib><creatorcontrib>Asadian, Peyman</creatorcontrib><creatorcontrib>Li, Peng</creatorcontrib><creatorcontrib>Thorling, Camilla A.</creatorcontrib><creatorcontrib>Robertson, Thomas A.</creatorcontrib><creatorcontrib>Fletcher, Linda M.</creatorcontrib><creatorcontrib>Crawford, Darrell H.G.</creatorcontrib><creatorcontrib>Roberts, Michael S.</creatorcontrib><creatorcontrib>School of Medicine</creatorcontrib><creatorcontrib>Department of Gastroenterology and Hepatology and School of Medicine</creatorcontrib><creatorcontrib>University of Queensland</creatorcontrib><creatorcontrib>School of Pharmacy & Medical Science</creatorcontrib><creatorcontrib>Therapeutics Research Centre</creatorcontrib><creatorcontrib>Princess Alexandra Hospital</creatorcontrib><creatorcontrib>University of South Australia</creatorcontrib><title>Liver Fibrosis Impairs Hepatic Pharmacokinetics of Liver Transplant Drugs in the Rat Model</title><title>DRUG METABOLISM AND PHARMACOKINETICS</title><addtitle>Drug Metab Pharmacokinet</addtitle><description>This study aims to investigate hepatic pharmacokinetics of the four most common drugs (metoprolol, omeprazole, spironolactone, and furosemide) given to patients undergoing liver transplantation before surgery. The investigation was carried out in CCl4-induced fibrotic perfused rat livers and the results were compared to those in normal rat liver. Drug outflow fraction-time profiles were obtained after bolus injection into a single-pass-perfused normal or fibrotic rat liver. The pharmacokinetic parameters were estimated using previously developed barrier-limited and space-distributed models. The results showed a marked increase in the liver fibrosis index for CCl4-treated rats compared to controls (p<0.05). The extraction ratios (E) for all drugs were significantly lower (p<0.05) in fibrotic than in normal livers and the decrease in E was consistent with the decrease in intrinsic clearance and permeability-surface area product. In addition, other than for furosemide, the mean transit times for all drugs were significantly longer (p<0.01) in the fibrotic livers than in normal livers. Pharmacokinetic model and stepwise regression analyses suggest that these differences arise from a reduction in both the transport of drugs across the basolateral membrane and their metabolic clearance and were in a manner similar to those previously found for another group of drugs.</description><subject>Animals</subject><subject>Bile Ducts, Intrahepatic - drug effects</subject><subject>Bile Ducts, Intrahepatic - physiopathology</subject><subject>Carbon Tetrachloride - pharmacology</subject><subject>Extracellular Space - drug effects</subject><subject>furosemide</subject><subject>Furosemide - metabolism</subject><subject>Furosemide - pharmacokinetics</subject><subject>hepatic pharmacokinetics</subject><subject>Liver - drug effects</subject><subject>Liver - metabolism</subject><subject>Liver - pathology</subject><subject>Liver - physiopathology</subject><subject>Liver Cirrhosis - chemically induced</subject><subject>Liver Cirrhosis - metabolism</subject><subject>Liver Cirrhosis - physiopathology</subject><subject>liver fibrosis</subject><subject>Liver Transplantation</subject><subject>Male</subject><subject>metoprolol</subject><subject>Metoprolol - metabolism</subject><subject>Metoprolol - pharmacokinetics</subject><subject>Models, Biological</subject><subject>omeprazole</subject><subject>Omeprazole - metabolism</subject><subject>Omeprazole - pharmacokinetics</subject><subject>Organ Size - drug effects</subject><subject>Oxygen Consumption - drug effects</subject><subject>Pharmaceutical Preparations - metabolism</subject><subject>Pharmacokinetics</subject><subject>propranolol</subject><subject>Propranolol - metabolism</subject><subject>Propranolol - pharmacokinetics</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>spironolactone</subject><subject>Spironolactone - metabolism</subject><subject>Spironolactone - pharmacokinetics</subject><subject>Transplantation Conditioning</subject><subject>Water - metabolism</subject><issn>1347-4367</issn><issn>1880-0920</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMFu1TAQRS0EoqXwBUjIO1YpYzuxkwUL1NLXildRPZUNG8uxHeo2iVM7qcTfM1EKSxb22DN3rmYOIe8ZnHImxCc3TA-n59c33woGxWFXgGAvyDGrayig4fAS36JURSmkOiJvcr4HEKIq-WtyxKFWion6mPzchyef6EVoU8wh06thMiFleuknMwdLb-5MGoyND2H0-M80dnRruU1mzFNvxpmep-VXpmGk852nBzPT6-h8_5a86kyf_bvneEJ-XHy9Pbss9t93V2df9oWVUsyFMMqBU50FZlwNtu261gJvalaBqpqOOYl1zlsGbV22rlK8EkxhqnFS8lqckI-b75Ti4-LzrIeQre9xNB-XrJUsK9FIJVEpNqXFZXPynZ5SGEz6rRnolalemeqV6Zo57DQyxa4Pz_5LO3j3r-cvRBTsNgFWgzV9HHukpe_jkkZcXNvIBj-bFjvQFYBXUGHAU5Z8vRomGuCco9Pnzckjr6fgk842-NGib_J21i6G_476ByEonxk</recordid><startdate>20100101</startdate><enddate>20100101</enddate><creator>Zou, Yu-Hong</creator><creator>Liu, Xin</creator><creator>Khlentzos, Alexander M.</creator><creator>Asadian, Peyman</creator><creator>Li, Peng</creator><creator>Thorling, Camilla A.</creator><creator>Robertson, Thomas A.</creator><creator>Fletcher, Linda M.</creator><creator>Crawford, Darrell H.G.</creator><creator>Roberts, Michael S.</creator><general>Elsevier Ltd</general><general>Japanese Society for the Study of Xenobiotics</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20100101</creationdate><title>Liver Fibrosis Impairs Hepatic Pharmacokinetics of Liver Transplant Drugs in the Rat Model</title><author>Zou, Yu-Hong ; Liu, Xin ; Khlentzos, Alexander M. ; Asadian, Peyman ; Li, Peng ; Thorling, Camilla A. ; Robertson, Thomas A. ; Fletcher, Linda M. ; Crawford, Darrell H.G. ; Roberts, Michael S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c663t-3a7d0d7fc01ad80cbffbc0298150759f1d6d0d22b10b84bd57253170d29d66283</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Bile Ducts, Intrahepatic - drug effects</topic><topic>Bile Ducts, Intrahepatic - physiopathology</topic><topic>Carbon Tetrachloride - pharmacology</topic><topic>Extracellular Space - drug effects</topic><topic>furosemide</topic><topic>Furosemide - metabolism</topic><topic>Furosemide - pharmacokinetics</topic><topic>hepatic pharmacokinetics</topic><topic>Liver - drug effects</topic><topic>Liver - metabolism</topic><topic>Liver - pathology</topic><topic>Liver - physiopathology</topic><topic>Liver Cirrhosis - chemically induced</topic><topic>Liver Cirrhosis - metabolism</topic><topic>Liver Cirrhosis - physiopathology</topic><topic>liver fibrosis</topic><topic>Liver Transplantation</topic><topic>Male</topic><topic>metoprolol</topic><topic>Metoprolol - metabolism</topic><topic>Metoprolol - pharmacokinetics</topic><topic>Models, Biological</topic><topic>omeprazole</topic><topic>Omeprazole - metabolism</topic><topic>Omeprazole - pharmacokinetics</topic><topic>Organ Size - drug effects</topic><topic>Oxygen Consumption - drug effects</topic><topic>Pharmaceutical Preparations - metabolism</topic><topic>Pharmacokinetics</topic><topic>propranolol</topic><topic>Propranolol - metabolism</topic><topic>Propranolol - pharmacokinetics</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>spironolactone</topic><topic>Spironolactone - metabolism</topic><topic>Spironolactone - pharmacokinetics</topic><topic>Transplantation Conditioning</topic><topic>Water - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zou, Yu-Hong</creatorcontrib><creatorcontrib>Liu, Xin</creatorcontrib><creatorcontrib>Khlentzos, Alexander M.</creatorcontrib><creatorcontrib>Asadian, Peyman</creatorcontrib><creatorcontrib>Li, Peng</creatorcontrib><creatorcontrib>Thorling, Camilla A.</creatorcontrib><creatorcontrib>Robertson, Thomas A.</creatorcontrib><creatorcontrib>Fletcher, Linda M.</creatorcontrib><creatorcontrib>Crawford, Darrell H.G.</creatorcontrib><creatorcontrib>Roberts, Michael S.</creatorcontrib><creatorcontrib>School of Medicine</creatorcontrib><creatorcontrib>Department of Gastroenterology and Hepatology and School of Medicine</creatorcontrib><creatorcontrib>University of Queensland</creatorcontrib><creatorcontrib>School of Pharmacy & Medical Science</creatorcontrib><creatorcontrib>Therapeutics Research Centre</creatorcontrib><creatorcontrib>Princess Alexandra Hospital</creatorcontrib><creatorcontrib>University of South Australia</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>DRUG METABOLISM AND PHARMACOKINETICS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zou, Yu-Hong</au><au>Liu, Xin</au><au>Khlentzos, Alexander M.</au><au>Asadian, Peyman</au><au>Li, Peng</au><au>Thorling, Camilla A.</au><au>Robertson, Thomas A.</au><au>Fletcher, Linda M.</au><au>Crawford, Darrell H.G.</au><au>Roberts, Michael S.</au><aucorp>School of Medicine</aucorp><aucorp>Department of Gastroenterology and Hepatology and School of Medicine</aucorp><aucorp>University of Queensland</aucorp><aucorp>School of Pharmacy & Medical Science</aucorp><aucorp>Therapeutics Research Centre</aucorp><aucorp>Princess Alexandra Hospital</aucorp><aucorp>University of South Australia</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Liver Fibrosis Impairs Hepatic Pharmacokinetics of Liver Transplant Drugs in the Rat Model</atitle><jtitle>DRUG METABOLISM AND PHARMACOKINETICS</jtitle><addtitle>Drug Metab Pharmacokinet</addtitle><date>2010-01-01</date><risdate>2010</risdate><volume>25</volume><issue>5</issue><spage>442</spage><epage>449</epage><pages>442-449</pages><issn>1347-4367</issn><eissn>1880-0920</eissn><abstract>This study aims to investigate hepatic pharmacokinetics of the four most common drugs (metoprolol, omeprazole, spironolactone, and furosemide) given to patients undergoing liver transplantation before surgery. The investigation was carried out in CCl4-induced fibrotic perfused rat livers and the results were compared to those in normal rat liver. Drug outflow fraction-time profiles were obtained after bolus injection into a single-pass-perfused normal or fibrotic rat liver. The pharmacokinetic parameters were estimated using previously developed barrier-limited and space-distributed models. The results showed a marked increase in the liver fibrosis index for CCl4-treated rats compared to controls (p<0.05). The extraction ratios (E) for all drugs were significantly lower (p<0.05) in fibrotic than in normal livers and the decrease in E was consistent with the decrease in intrinsic clearance and permeability-surface area product. In addition, other than for furosemide, the mean transit times for all drugs were significantly longer (p<0.01) in the fibrotic livers than in normal livers. Pharmacokinetic model and stepwise regression analyses suggest that these differences arise from a reduction in both the transport of drugs across the basolateral membrane and their metabolic clearance and were in a manner similar to those previously found for another group of drugs.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>20877138</pmid><doi>10.2133/dmpk.DMPK-10-RG-031</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1347-4367 |
| ispartof | DRUG METABOLISM AND PHARMACOKINETICS, 2010-01, Vol.25 (5), p.442-449 |
| issn | 1347-4367 1880-0920 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_764539676 |
| source | J-STAGE Free; MEDLINE; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Animals Bile Ducts, Intrahepatic - drug effects Bile Ducts, Intrahepatic - physiopathology Carbon Tetrachloride - pharmacology Extracellular Space - drug effects furosemide Furosemide - metabolism Furosemide - pharmacokinetics hepatic pharmacokinetics Liver - drug effects Liver - metabolism Liver - pathology Liver - physiopathology Liver Cirrhosis - chemically induced Liver Cirrhosis - metabolism Liver Cirrhosis - physiopathology liver fibrosis Liver Transplantation Male metoprolol Metoprolol - metabolism Metoprolol - pharmacokinetics Models, Biological omeprazole Omeprazole - metabolism Omeprazole - pharmacokinetics Organ Size - drug effects Oxygen Consumption - drug effects Pharmaceutical Preparations - metabolism Pharmacokinetics propranolol Propranolol - metabolism Propranolol - pharmacokinetics Rats Rats, Wistar spironolactone Spironolactone - metabolism Spironolactone - pharmacokinetics Transplantation Conditioning Water - metabolism |
| title | Liver Fibrosis Impairs Hepatic Pharmacokinetics of Liver Transplant Drugs in the Rat Model |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-27T19%3A27%3A48IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Liver%20Fibrosis%20Impairs%20Hepatic%20Pharmacokinetics%20of%20Liver%20Transplant%20Drugs%20in%20the%20Rat%20Model&rft.jtitle=DRUG%20METABOLISM%20AND%20PHARMACOKINETICS&rft.au=Zou,%20Yu-Hong&rft.aucorp=School%20of%20Medicine&rft.date=2010-01-01&rft.volume=25&rft.issue=5&rft.spage=442&rft.epage=449&rft.pages=442-449&rft.issn=1347-4367&rft.eissn=1880-0920&rft_id=info:doi/10.2133/dmpk.DMPK-10-RG-031&rft_dat=%3Cproquest_cross%3E764539676%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=764539676&rft_id=info:pmid/20877138&rft_els_id=S1347436715300549&rfr_iscdi=true |