Pharmacokinetics and clearance processes of UK-279,276 (rNIF) in rat and dog: comparison with human data.
UK-279,276, or recombinant neutrophil inhibitory factor (rNIF), is a glycoprotein that binds to the human CD11b receptor (IC(50) = <0.5 nM) and inhibits neutrophil binding to vascular endothelial cells. In dogs, the pharmacokinetics of UK-279,276 are non-linear with clearance slowing as dose increases (apparent clearance 0.06 ml min(-1) kg(-1) at 0.l mg kg(-1) decreasing to 0.02 ml min(-1) kg(-1) at 2 mg kg(-1)). The observations are in keeping with human pharmacokinetic data. In rats, clearance is linear (0.07-0.13 ml min(-1) kg(-1)) across a similar dose range (0.006-2.25 mg kg(-1)) compared with dogs and humans. These data indicate that two clearance processes act on UK-279,276 in dogs and humans, but only one clearance process occurs in rats. A non-saturable, low-affinity/high-capacity clearance process is present in all animal species studied as well as in human, and it is believed to be hepatic uptake mediated by the asialoglycoprotein receptor. A second, saturable, clearance process is present in dogs and humans that is not apparent in the rat. This high-affinity/low-capacity process is thought to be mediated by interaction with the CD11b receptor, which is the pharmacological target for this molecule. This hypothesis is supported by the marked species differences seen for the affinity of CD11b for UK-279,276, with dogs and humans having high-affinity (IC(50) = <0.5 nM), whilst the rat affinity is low (IC(50) = 134 nM).
Webster
R
R
Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Sandwich, UK. Rob_Webster@Pfizer.com
Edgington
A
A
Phipps
J
J
Walker
D
D