Internalization: what does it tell us about pharmacokinetic and pharmacodynamic properties of an antagonist?
Chemokine receptors play an important role in trafficking leukocytes within the body, a process that depends on expression of the receptors on the cell surface. Expression levels are regulated by the rate of internalizing receptor compared to the rate of recycling/recovering receptor. Internalization is commonly induced by binding of agonists to their receptors that in turn use clathrin-coated pits or caveolae to internalize. Joplin and colleagues describe a novel usage of internalization assays to determine pharmacokinetic/pharmacodynamic relationships of an antagonist on CXCR3 in a murine system. Intriguingly their results show that internalization assays give robust data about the pharmacokinetics/pharmacodynamics of different agonists and antagonists in an in vivo model. This kind of assay will allow investigations of the pharmacological properties of agonists and antagonists in a completely different setting and also give new insight into the regulation of cell surface expression of chemokine receptors and other G protein-coupled receptors, which can lead to potential novel therapeutic targets.
Mueller
A
A
School of Chemical Sciences and Pharmacy, University of East Anglia, University Plain, Norwich, UK. anja.mueller@uea.ac.uk
D000818:Animals; D016503:Drug Delivery Systems; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008954:Models, Biological; D010599:Pharmacokinetics; D010600:Pharmacology; D054387:Receptors, CXCR / Q000037:antagonists & inhibitors* / Q000235:genetics
D054387:Receptors, CXCR