The Use of Radiolabeled Compounds for ADME Studies in Discovery and Exploratory Development

Abstract

Radiolabeled compounds are excellent investigative tools and widely used to carry out ADME studies during drug discovery and development stages. The most commonly used radioisotopes are 14C and 3H. 3H materials are generally easier to synthesize than 14C materials. Therefore, a variety of probes and substrates used in in vitro assays are labeled with 3H. Since synthesis of 14C material requires intensive resources, it is usually not available until after a molecule is considered for potential development or after the molecule enters the development phase. Improvement in the technology in radiochemistry has enabled the use of radiolabeled compounds earlier in pre-clinical and clinical development to address mechanistic issues. For in vitro studies, radiolabeled probes are utilized to test affinity with various transporters, to perform metabolism comparison among species and to assess possible formation of reactive metabolites. For in vivo studies, radiolabeled compounds are employed to identify and elucidate metabolites formed, to investigate the extent of absorption, bioavailability, tissue distribution, mass balance, routes of excretion, and pre-systemic metabolism. Due to the significant impact of radiolabeled studies on drug development, these studies will be performed earlier than have been in the past and will continue to be an integral part of drug discovery and development.

Metabolism and Disposition of Dasatinib after Oral Administration to Humans

“…In drug development, these studies are performed with either C-14 or tritium-labeled material to provide detailed quantitative information on circulating metabolites, the extent of metabolism, and routes of excretion for drug and its metabolites (Marathe et al, 2004). This study describes the metabolism and disposition of […”

Excretion of [3H]triptolide and its metabolites in rats after oral administration

“…Excretion results may elucidate the relationship between the pharmacokinetic results and the status of the metabolic enzymes, transporters, etc. Excretion recovery studies using radiolabeled compounds conducted in laboratory animals and humans are standard components in the development of novel drug treatments [12] . The objective of the current study was to investigate the…”

Synthesis and biological evaluation of 131I‐labelled pyronaridine

“…This non-invasive imaging approach provides a powerful research tool for the discovery and development of new drugs, providing information which cannot be obtained by other means. 11 Radiolabelling of drugs can be accomplished by two methods. Direct labelling method involves a reaction between a drug and a radioisotope to produce a radiolabelled drug whereas, the indirect labelling method employs the use of spacers or linkers to attach a radioisotope to a drug.…”