Document Detail

Characterization of the postglomerular renal metabolism of lepirudin in healthy volunteers.
MedLine Citation:
PMID:  15140582     Owner:  NLM     Status:  MEDLINE    
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.
Michael Kautzleben; Günter Stein; Heide Sperschneider; Götz Nowak
Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Thrombosis research     Volume:  113     ISSN:  0049-3848     ISO Abbreviation:  Thromb. Res.     Publication Date:  2004  
Date Detail:
Created Date:  2004-05-13     Completed Date:  2004-12-07     Revised Date:  2012-07-11    
Medline Journal Info:
Nlm Unique ID:  0326377     Medline TA:  Thromb Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  187-95     Citation Subset:  IM    
Copyright Information:
Copyright 2004 Elsevier Ltd.
Research Unit "Pharmacological Haemostaseology", Friedrich Schiller, University, Jena, Germany.
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MeSH Terms
Amino Acid Sequence
Anticoagulants / metabolism*
Blood Coagulation Tests
Chromatography, High Pressure Liquid
Endopeptidases / pharmacology
Fibrinolytic Agents / pharmacology
Hirudins / administration & dosage,  analogs & derivatives*,  chemistry,  metabolism*,  urine
Injections, Intravenous
Kidney Tubules, Proximal / metabolism*
Mass Spectrometry
Molecular Weight
Proteins / analysis
Recombinant Proteins / administration & dosage,  chemistry,  metabolism*,  urine
Reg. No./Substance:
0/Anticoagulants; 0/Fibrinolytic Agents; 0/Hirudins; 0/Proteins; 0/Recombinant Proteins; 0/lepirudin; EC 3.4.-/Endopeptidases; EC 3.4.24.-/ecarin

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