The Application of Stable Isotopes to Studies of Drug Bioavailability and Bioequivalence

Abstract

The increased availability of chemical intermediates and automated instrumentation has resulted in expanded use of stable isotopes for bioavailability and bioequivalence studies in recent years. Initially, stable isotopes were confined to the labeling of mass internal standard compounds for gas chromatography/mass spectrometry. More recently, their in vivo use has expanded and proved to be a powerful pharmacologic tool. The lack of toxicity of stable isotopes, particularly deuterium and carbon‐13, make them ideally suited for human studies. The primary advantage of the isotopic methods is that the drug can be administered concomitantly either by two routes (e.g., parenteral and oral) or in two formulations (e.g., solution and solid dosage). Thus, a single set of blood samples serves to describe the time course of the routes or formulations being compared. The concomitant administration reduces variability inherent in dual administration, the single assay for both forms further reduces variation, and the method minimizes both drug exposure and discomfort to the subject. In addition to single‐dose administration, in which two routes or dosage forms are compared, the technique is well suited to “pulse” administration, wherein the kinetics of a single dose, during multiple or chronic dosing regimens, can be compared with single‐dose kinetics.