Vol. 298, Issue 3, 886-893, September 2001

Pharmacokinetics and Tissue Distribution of SB-251353, a Novel Human CXC Chemokine, after Intravenous Administration to Mice

Timothy W. Hepburn, Timothy K. Hart, Vicki L. Horton, Teresa S. Sellers, LeeAnn P. Tobia, James J. Urbanski, Wei Shi and Charles B. Davis

Drug Metabolism and Pharmacokinetics (T.W.H., V.L.H., L.P.T, J.J.U., W.S, C.B.D.) and Department of Safety Assessment (T.K.H., T.S.S.), GlaxoSmithKline, King of Prussia, Pennsylvania

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 (0.1-250 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 distribution volumes were high (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.