Role of sialylation in determining the pharmacokinetics of neutrophil inhibitory factor (NIF) in the Fischer 344 rat

1. Recombinant neutrophil inhibitory factor (NIF) is a glycoprotein. Its am ino acid sequence remains constant and has a molecular weight of 28.9 kD. H owever, similar to 40 % of the total molecular weight consists of glycans w ith variable structure. 2. The pharmacokinetics of Il different NIF batches with varying extents an d patterns of sialylation have been investigated in the Fischer 344 rat fol lowing intravenous administration. These data indicate that reducing the ex tent of NIF sialylation reduces the half-life of the molecule due to an inc rease in the systemic clearance. Also, an increase in the number of unsialy lated or neutral glycans may increase the volume of distribution of NIF, al though this effect is marginal. 3. Isolated perfused rat liver (IPRL) investigations have shown that sialyl ated NIF has a low hepatic extraction (< 1%), while asialo NIF has an extra ction that is > 20-fold higher. Go-administration of asialo NIF with asialo fetuin (a protein cleared by hepatic asialoglycoprotein receptor (possibly galactose)-mediated uptake reduced the hepatic extraction of asialo NIF. 4. These data suggest that NIF molecules that have free sugar moieties (pos sibly galactose) interact with an asialoglycoprotein receptor (possibly gal actose-mediated) in the liver (parenchymal cells/hepatocytes). Interaction with this receptor leads to cellular internalization and degradation.