| Characterization of the postglomerular renal metabolism of lepirudin in healthy volunteers. | |
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MedLine Citation:
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PMID: 15140582 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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INTRODUCTION: The anticoagulant r-hirudin lepirudin is eliminated exclusively via the kidneys. We examined the C-terminal amino acid degradation of lepirudin by the proximal kidney tubulus cells in humans as well as the antithrombotic efficacy of the metabolites and quantified the metabolite portions. MATERIALS AND METHODS: In vitro metabolites of lepirudin were produced by adding 250 microg lepirudin to urine of three healthy volunteers and a concentration of 100 ml fresh urine to 1.5 ml and subsequent separation by high performance liquid chromatography. Anticoagulant activities of the mass spectrometrically identified metabolites were measured by ecarin clotting time and protein determination with bicinchoninic acid. In 10 healthy volunteers 1 mg lepirudin was administered intravenously, urine was collected during the following 2 h. The urine amount containing 50 microg lepirudin measured by ecarin clotting time was enzyme-inactivated and measured analogously to the in vitro samples. RESULTS: The in vitro generated metabolites were shortened amino acid by amino acid at the C-terminal end, up to five amino acids. Their anticoagulant activity was reduced to 92.6% (M64), 80.1% (M63) and 74.4% (M60,61,62) in comparison to lepirudin. Lepirudin (57.9 +/- 8.6%) was eliminated unchanged via the kidneys. Identical to the in vitro situation metabolite fragments were built in the distribution M64 = 8.1 +/- 5.7%, M63 = 21.1 +/- 6.5%, and M60,61,62 = 12.9 +/- 4.5%. CONCLUSIONS: Lepirudin is metabolized spontaneously in more than 10-fold concentrated urine. Metabolization of lepirudin takes place in the proximal tubulus cells as well. In vitro, the degradation takes place amino acid by amino acid, but in vivo even dipeptides and perhaps tripeptides are degraded. |
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Authors:
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Michael Kautzleben; Günter Stein; Heide Sperschneider; Götz Nowak |
Publication Detail:
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Type: Comparative Study; Journal Article |
Journal Detail:
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Title: Thrombosis research Volume: 113 ISSN: 0049-3848 ISO Abbreviation: Thromb. Res. Publication Date: 2004 |
Date Detail:
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Created Date: 2004-05-13 Completed Date: 2004-12-07 Revised Date: 2012-07-11 |
Medline Journal Info:
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Nlm Unique ID: 0326377 Medline TA: Thromb Res Country: United States |
Other Details:
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Languages: eng Pagination: 187-95 Citation Subset: IM |
Copyright Information:
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Copyright 2004 Elsevier Ltd. |
Affiliation:
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Research Unit "Pharmacological Haemostaseology", Friedrich Schiller, University, Jena, Germany. Michael.Kautzleben@web.de |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adult Amino Acid Sequence Anticoagulants / metabolism* Blood Coagulation Tests Chromatography, High Pressure Liquid Endopeptidases / pharmacology Female Fibrinolytic Agents / pharmacology Hirudins / administration & dosage, analogs & derivatives*, chemistry, metabolism*, urine Humans Injections, Intravenous Kidney Tubules, Proximal / metabolism* Male Mass Spectrometry Molecular Weight Proteins / analysis Recombinant Proteins / administration & dosage, chemistry, metabolism*, urine |
| Chemical | |
Reg. No./Substance:
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0/Anticoagulants; 0/Fibrinolytic Agents; 0/Hirudins; 0/Proteins; 0/Recombinant Proteins; 0/lepirudin; EC 3.4.-/Endopeptidases; EC 3.4.24.-/ecarin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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