Kinetics of the metabolism of four PET radioligands in living minipigs

Most radioligands are substantially metabolised in peripheral organs during the course of positron emission tomography (PET) recordings. Accurate determination of plasma concentrations of unmetabolised radioligands is often important for quantification of data from PET studies. The fractions of untransformed radioligand and radioactive metabolites in plasma extracts must then be measured. Temporal changes in these fractions are influenced by the rate constant of appearance of total radioactive metabolites in plasma (apparent rate constant of metabolism in plasma, k(0)) and the net rate constant of elimination of all radioactive metabolites from plasma (k(-I)). In order to clarify the relationship between radioligand fractions and rate constants, plasma samples collected from Gottingen minipigs during PET recordings using four different binding site ligands were analysed by radio high performance liquid chromatography. The calculated plasma concentrations of parent compounds and their radioactive metabolites were used to calculate k(0) and k(-1) for C-11-labelled NNC 112, NS 2214, PK 11195 and raclopride in minipigs using a novel application of the tissue-slope intercept plot. In general, the apparent rate constant of metabolism in plasma was found to be greater in the minipig than in man. The reported kinetic analysis enables the apparent metabolism of PET radioligands in plasma to be quantified. (C) 2001 Elsevier Science Inc. All rights reserved.