Recommendations on the Use of Multiple Labels in Human Mass Balance Studies

Abstract

The administration of radiolabeled drug candidates is considered the gold standard in absorption, distribution, metabolism and excretion (ADME) studies for small molecule drugs, since it allows facile and accurate quantification of parent drug, metabolites and total drug related material independent of the compound structure. The choice of the position of the radiolabel, typically 14 C or 3 H, is critical to obtain relevant information. Sometimes a biotransformation reaction may lead to cleavage of a part of the molecule. As a result, only the radiolabeled portion can be followed while information on the fate of the non-labeled metabolite may be lost. Synthesis and administration of two or more radiolabeled versions of the parent drug as a mixture or in separate studies may resolve this issue but comes with additional challenges. In this paper we address the questions that may be considered to help make the right choice whether to use single or a multiple radiolabel approach, discuss pros and cons of different multiple labeling strategies that can be taken as well as alternative methods that allow the non-labeled part of the molecule to be followed.