In Vitro and In Vivo Studies on the Pharmacokinetics and Metabolism of PNA Constructs in Rodents

Abstract

This chapter describes fast and simple methods for early evaluation of the pharmacokinetic parameters of peptide nucleic acid (PNA) oligomers in vitro and in vivo. The in vitro methods are based on incubation of the PNAs with plasma and selected tissue homogenates from rodents. These high-throughput screening assays provide valuable information on biological stability and metabolic pathways in the early structure optimization and lead candidate selection processes. Further, a method is presented for extraction and analysis of PNA oligomers from biological samples (plasma/ serum, bile, urine, and tissue) obtained from animal studies. Design of a pilot pharmacokinetic study in rodents is described for preliminary evaluation of key pharmacokinetic parameters such as systemic clearance, volume of distribution, and elimination half-life. Application of both in vitro and in vivo methodologies are demonstrated using a 12-mer PNA.