Use of Radiolabeled Compounds in Drug Metabolism and Pharmacokinetic Studies

TLDR

Understanding drug fate in humans and the relevance of animal models is essential, so in vitro and in vivo studies are performed to elucidate ADME properties, and although LC/MS is common, radiolabeled molecules remain necessary for quantifying metabolites and assessing retention and excretion without relying on structural or MS ionization data. The paper aims to describe AstraZeneca’s Isotope Chemistry activities and provide an overview of common methods for preparing 14C and 3H labeled drug candidates. It also presents drug metabolism and pharmacokinetic studies using radiolabeled candidates, including in‑house examples. The authors conclude by outlining strategic changes to their use of radiolabeled compounds, emphasizing a shift toward delaying in‑vivo studies with radiolabeled drugs.

Abstract

As part of the drug discovery and development process, it is important to understand the fate of the drug candidate in humans and the relevance of the animal species used for preclinical toxicity and pharmacodynamic studies. Therefore, various in vitro and in vivo studies are conducted during the different stages of the drug development process to elucidate the absorption, distribution, metabolism, and excretion properties of the drug candidate. Although state-of-the-art LC/MS techniques are commonly employed for these studies, radiolabeled molecules are still frequently required for the quantification of metabolites and to assess the retention and excretion of all drug related material without relying on structural information and MS ionization properties. In this perspective, we describe the activities of Isotope Chemistry at AstraZeneca and give a brief overview of different commonly used approaches for the preparation of 14C- and 3H-labeled drug candidates. Also various drug metabolism and pharmacokinetic studies utilizing radiolabeled drug candidates are presented with in-house examples where relevant. Finally, we outline strategic changes to our use of radiolabeled compounds in drug metabolism and pharmacokinetic studies, with an emphasis on delaying of in vivo studies employing radiolabeled drug molecules.