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Studies on the pharmacokinetics and pharmacodynamics of recombinant hirudin (rHV2-Lys 47) after intravenous and subcutaneous administration in dogs.
- Source :
-
Thrombosis research [Thromb Res] 1993 Feb 01; Vol. 69 (3), pp. 259-69. - Publication Year :
- 1993
-
Abstract
- In recent years, the pharmacological and biochemical characterization of hirudins has taken a major upswing due to the availability of this natural polypeptide in recombinant form. Despite this, the current knowledge on the pharmacokinetics and pharmacodynamics of recombinant hirudin (rH) appears to be incomplete. The present study was designed to investigate the relationship between plasma concentrations of rH with corresponding antithrombin responses after intravenous (i.v.) and subcutaneous (s.c.) administration in dogs. Four male, Mongrel dogs were each injected with an i.v. (bolus) dose (1 mg/kg) of one specific variant of rH, i.e. rH with a lysine residue in position 47 (rHV2-Lys 47). The dogs were injected with a s.c. dose (1 mg/kg) of rHV2-Lys 47 after one week. After each dose, blood was collected at different time intervals, plasma separated and stored at -70 degrees C. Plasma concentrations of rHV2-Lys 47 were determined using an enzyme-linked immunosorbent assay (ELISA) method and pharmacokinetic parameters were determined using standard non-compartmental methods. The ex vivo antithrombin activity of the drug was measured using activated partial thromboplastin time (APTT), calcium-thrombin time (Ca++TT) and a chromogenic anti-IIa assay. The results from this study indicate that the pharmacokinetic behavior of rHV2-Lys 47 is strongly influenced by the route of administration. In all three functional assays used, a significant correlation was obtained after i.v. administration between plasma concentrations and corresponding responses over the time period of the study when compared to s.c. administration. The results are indicative of a probable structural and functional modification of this rH variant after s.c. administration which may be responsible for the altered pharmacokinetics and pharmacodynamics after s.c. dosing.
- Subjects :
- Animals
Biological Availability
Cattle
Chromogenic Compounds metabolism
Enzyme-Linked Immunosorbent Assay
Hirudins administration & dosage
Hirudins blood
Hirudins pharmacokinetics
Hirudins pharmacology
Injections, Intravenous
Injections, Subcutaneous
Male
Oligopeptides metabolism
Partial Thromboplastin Time
Recombinant Fusion Proteins administration & dosage
Recombinant Fusion Proteins blood
Recombinant Fusion Proteins pharmacokinetics
Recombinant Fusion Proteins pharmacology
Recombinant Proteins administration & dosage
Recombinant Proteins blood
Recombinant Proteins pharmacokinetics
Recombinant Proteins pharmacology
Thrombin Time
Hirudins analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 0049-3848
- Volume :
- 69
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Thrombosis research
- Publication Type :
- Academic Journal
- Accession number :
- 8475476
- Full Text :
- https://doi.org/10.1016/0049-3848(93)90023-h