Pivotal to the process of drug development is an understanding of how the drug is absorbed into the body, its distribution throughout the body as well as its metabolism and excretion from the body (ADME studies). In order to follow the metabolic fate of a drug in the human body, the drug is 14C-labelled, which acts like a “tag”, and by following the radioactivity, the metabolic fate of the drug can be traced.
There are however, severe restrictions on the levels of radioactivity that can be administered to humans and the resulting radiation exposure. In the past, the use of 14C in human metabolism studies was very challenging because sufficient levels of radioactivity had to be administered in order to detect the 14C-labelled drug. This was not always possible due to the legal restrictions and hence a much more sensitive method of following 14C in the body was required. The advent of AMS provided the answer to this problem.
One of the issues ADME studies are designed to address is the metabolic stability of a drug. Although some drugs are metabolically stable others are extensively metabolised over time. The extent of metabolism is determined experimentally by chromatographically profiling samples such as excreta and plasma but choosing appropriate time-points for the profiles can be a little hit and miss. The extent of systemic metabolites can be assessed by comparing the total 14C-concentration and the concentration of parent drug (measured by a “cold” method, such as LC-MS). The degree to which the pharmacokinetic curves differ between total 14C and parent drug shows the extent of systemic metabolism and therefore the choice of time-points for profiling becomes much easier.
Using similar techniques, the pharmacokinetics attained from oral and intravenous dose administrations can be compared and this can indicate the extent of first-pass metabolism. This effect occurs when the drug is metabolised by the liver (or sometimes in the GI tract) so that the amount of drug that reaches systemic circulation is severely reduced.
Examples of metabolism studies using AMS will be presented along with the underlying pharmacokinetic principals.
See more of AMS in Low Dose Bioscience Workshop
See more of The 10th International Conference on Accelerator Mass Spectrometry (September 5-10, 2005)