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Pharmacokinetics and whole body distribution of elastase derived angiostatin (k1‐3) in rats
Author(s) -
Molema Grietje,
van VeenHof Ingrid,
van LoenenWeemaes Annemiek,
Proost Johannes H.,
de Leij Lou F.M.H.,
Meijer Dirk K.F.
Publication year - 2000
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/1097-0215(20010101)91:1<1::aid-ijc1001>3.0.co;2-5
Subject(s) - angiostatin , kidney , pharmacokinetics , chemistry , medicine , endocrinology , distribution (mathematics) , spleen , enterohepatic circulation , pathology , biology , metabolism , angiogenesis , mathematical analysis , mathematics
In the current study, we determined short‐term pharmacokinetics and whole body distribution of elastase derived angiostatin [angiostatin (k1‐3) ] in rats after i.v. injection of radiolabelled protein. Since in gamma‐camera studies, no tumor specific angiostatin (k1‐3) accumulation was observed, general pharmacokinetics were studied in tumor free rats. By one‐compartment model fitting of the data, K m 7.3 ± 1.7 μg • ml −1 , V max 0.94 ± 0.19 μg • min −1 , V 1 10.9 ± 2.5 ml and intrinsic clearance (V max / K m ) 0.128 ml • min −1 were calculated. Of the injected dose (I.D.) of angiostatin (k1‐3) , 12.1 ± 2.1% per gram tissue was present in the kidneys 10 min after injection. Accumulation of angiostatin (k1‐3) was detectable in spleen, liver, lungs and heart 10 min after injection. Sixty minutes after injection, kidney associated angiostatin (k1‐3) had decreased, whereas in stomach and small intestines a small increase was seen. Immunohistochemical analysis demonstrated specific staining of interstitial cells of the kidney, liver Kupffer cells and endothelium of larger blood vessels of the lungs. Renal clearance of angiostatin (k1‐3) and/or fragments is a major route of elimination, whereas lack of accumulation of radioactivity in the faeces indicates little hepatic elimination or hepatic elimination followed by enterohepatic cycling of the protein's degradation products. Instant blood coagulation at the site of vascular activation and the occurrence of respiratory problems upon administration of higher doses of angiostatin (k1‐3) warrants further investigation of the protein's potential side effects. The data presented can be applied to study the relation between angiostatin (k1‐3) treatment regimens, blood concentration levels, anti‐tumor activity and harmful effects. Int. J. Cancer 91:1–7, 2001. © 2001 Wiley‐Liss, Inc.