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 truncate d form of the human CXC chemokine growth-related gene product beta, were st udied after intravenous administration to the mouse (0.1-250 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 distributi on volumes were high (greater than or equal to l/kg). Moderate binding to t he Duffy antigen/receptor for chemokines on erythrocytes was observed. Cons istent with the pharmacokinetic analysis, microscopic autoradiography showe d uptake into renal proximal tubule epithelial cells. Limited excretion of SB-251353 in the urine (<2%) was consistent with catabolism of the chemokin e 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 volume s. This first study of the disposition of a chemokine provides insight into mechanism of action and physiological factors that may influence chemokine pharmacodynamics.