Pharmacokinetics and Tissue Distribution of SB-251353, a Novel Human CXC Chemokine, after Intravenous Administration to Mice
The pharmacokinetics and tissue distribution of SB-251353, a novel truncated form of the human CXC chemokine growth-related gene product beta, were studied after intravenous administration to the mouse (0.1â250 mg/kg). At the lowest dose, the clearance exceeded blood flow to the kidney. As the dos...
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Published in | The Journal of pharmacology and experimental therapeutics Vol. 298; no. 3; pp. 886 - 893 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.09.2001
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Subjects | |
Online Access | Get full text |
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Summary: | The pharmacokinetics and tissue distribution of SB-251353, a novel truncated form of the human CXC chemokine growth-related
gene product beta, were studied after intravenous administration to the mouse (0.1â250 mg/kg). At the lowest dose, the clearance
exceeded blood flow to the kidney. As the dose increased, clearance approached the glomerular filtration rate in the mouse.
Clearance of this chemokine may be mediated by its pharmacologic receptor, CXCR2, via endocytosis with subsequent lysosomal
degradation, as has been observed for several growth and hematopoietic factors. Apparent distribution volumes were high (â¥1
l/kg). Moderate binding to the Duffy antigen/receptor for chemokines on erythrocytes was observed. Consistent with the pharmacokinetic
analysis, microscopic autoradiography showed uptake into renal proximal tubule epithelial cells. Limited excretion of SB-251353
in the urine (<2%) was consistent with catabolism of the chemokine in the tubules. Binding to hepatic sinusoids and connective
tissue in the dermis was observed. This possibly reflected interaction of SB-251353 with heparin sulfate proteoglycan and
may explain the large distribution volumes. This first study of the disposition of a chemokine provides insight into mechanism
of action and physiological factors that may influence chemokine pharmacodynamics. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0022-3565 1521-0103 |