| Hepatic distribution and clearance of antisense oligonucleotides in the isolated perfused rat liver. | |
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MedLine Citation:
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PMID: 9144742 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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PURPOSE: This study was conducted to investigate the impact of backbone modifications on the hepatobiliary disposition of oligonucleotides. METHODS: The disposition of backbone-modified antisense oligonucleotides [phosphorothioate (PS) and methylphosphonate (MP)] of the same base-length and sequence (5'-TAC-GCC-AAC-AGC-TCC-3'), complementary to the codon 12 activating mutation of Ki-ras, was investigated in the isolated perfused rat liver. Livers were perfused for 2 hr: perfusate and bile concentrations were analyzed by HPLC. Hepatocellular distribution was examined by measuring the amount of radiolabeled PS oligonucleotide associated with hepatocytes and Kupffer cells. Protein binding of the PS and MP oligonucleotides was determined in rat serum by ultrafiltration. RESULTS: MP oligonucleotide perfusate concentrations remained constant during the 2-hour perfusion. In contrast, PS oligonucleotide was eliminated slowly by the isolated perfused liver [CI = 1.05 +/- 0.21 mL/min; extraction ratio = 0.06 +/- 0.01]. Uptake of PS oligonucleotide by Kupffer cells appeared to exceed uptake by hepatocytes, based on standard cell separation techniques as well as confocal microscopy. The degree of protein binding in rat serum was greater for the PS oligonucleotide (79.9 +/- 2.2%) than for the MP oligonucleotide (53.0 +/- 4.7%). CONCLUSIONS: Backbone modifications significantly-influence the hepatic clearance of oligonucleotides. Uncharged MP oligonucleotides are not extracted by the isolated perfused rat liver, whereas the charged PS oligonucleotide is processed more readily. |
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Authors:
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A Nolting; R K DeLong; M H Fisher; E Wickstrom; G M Pollack; R L Juliano; K L Brouwer |
Publication Detail:
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Type: In Vitro; Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Pharmaceutical research Volume: 14 ISSN: 0724-8741 ISO Abbreviation: Pharm. Res. Publication Date: 1997 Apr |
Date Detail:
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Created Date: 1997-07-14 Completed Date: 1997-07-14 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 8406521 Medline TA: Pharm Res Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 516-21 Citation Subset: IM |
Affiliation:
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Division of Pharmaceutics, School of Pharmacy, University of North Carolina, Chapel Hill 27599, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Chromatography, High Pressure Liquid Liver / metabolism* Male Microscopy, Confocal Oligonucleotides, Antisense / pharmacokinetics* Perfusion Rats Rats, Sprague-Dawley |
| Grant Support | |
ID/Acronym/Agency:
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CA 47044/CA/NCI NIH HHS; CA 60139/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Oligonucleotides, Antisense |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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