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 amino acid sequence remains constant and has a molecular weight of 28.9 kD. However, approximately 40% of the total molecular weight consists of glycans with variable structure. 2. The pharmacokinetics of 11 different NIF batches with varying extents and patterns of sialylation have been investigated in the Fischer 344 rat following intravenous administration. These data indicate that reducing the extent of NIF sialylation reduces the half-life of the molecule due to an increase in the systemic clearance. Also, an increase in the number of unsialylated or neutral glycans may increase the volume of distribution of NIF, although this effect is marginal. 3. Isolated perfused rat liver (IPRL) investigations have shown that sialylated NIF has a low hepatic extraction (< 1%), while asialo NIF has an extraction that is > 20-fold higher. Co-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 (possibly galactose) interact with an asialoglycoprotein receptor (possibly galactose-mediated) in the liver (parenchymal cells/hepatocytes). Interaction with this receptor leads to cellular internalization and degradation.
Webster
R
R
Department of Drug Metabolism, Pfizer Central Research, Sandwich, UK. Rob_Webster@Sandwich.Pfizer.com
Taberner
J
J
Edgington
A
A
Guhan
S
S
Varghese
J
J
Feeney
H
H
Blocker
L
L
Jezequel
S G
SG
D000818:Animals; D019540:Area Under Curve; D005455:Fluorescent Antibody Technique; D006023:Glycoproteins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006207:Half-Life; D015801:Helminth Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D007601:Jugular Veins; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D019158:N-Acetylneuraminic Acid / Q000493:pharmacokinetics*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D009844:Oligosaccharides / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics
D006023:Glycoproteins; D015801:Helminth Proteins; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D009844:Oligosaccharides; D011994:Recombinant Proteins; C086581:NIF protein, Ancylostoma caninum; D019158:N-Acetylneuraminic Acid