PHARMACOKINETICS OF RECOMBINANT HUMAN TUMOR NECROSIS FACTOR-a IN RATS Effects of Size and Number of Doses and Nephrectomy

The serum pharmacokinetics of recombinant human tumor necrosis factor-a (rHuTNF) were determined in male and female rats under various conditions. The clearance of rHuTNF after iv administration was determined to be saturable over the dose range of 10-63 g/ kg. Multiple iv administration did not significantly change the clear-ance of rHuTNF. Nephrectomy significantly reduced but did not eliminate the clearance of rHuThF. The data suggest that sites other than the kidney also contribute to the elimination of rHuTNF. Female rats showed significantly reduced clearance of rHuTNF compared to male rats at all doses after single and multiple iv administration in control and nephrectomlzed animals. Tumor necrosis factor-a (TNF) ’ is an approximately 17,000-Da protein produced by various lymphoid cells including mac-rophages (1-3) and natural killer cells (4, 5). Although TNF displays a wide range of biological activities (6-13), its mai