STUDIES ON THE METABOLISM OF THE NOVEL ANTITUMOR AGENT 1]N-[2-(DIMETHYLAMINO)ETHYL]ACRIDINE-4-CARBOXAMIDE IN RATS AND HUMANS PRIOR TO PHASE-I CLINICAL-TRIALS

This study reports on the biodistribution and metabolism of the C-11-l abeled novel antitumor agent N-[2-(dimethylamino)ethyl]acridine-4-carb oxamide (DACA) (also known as NSC 601316) in rats (plasma and tissues) and humans (plasma). Information on plasma metabolites was uniquely o btained in humans Drier to Phase I clinical trial following i.v. injec tion of [C-11]DACA at tracer dose, DACA was labeled in the N-methyl po sition using no-carrier-added [C-11]iodomethane. Rapid high-performanc e liquid chromatography methods were developed for metabolite analysis of [C-11]DACA. The metabolism of [C-11]DACA was investigated in patie nts by plasma sampling, The biodistribution and metabolism of [C-11]DA CA was investigated in rats by plasma sampling, sacrifice experiments with tissue analyses, and imaging using positron emission tomography s canning, Analysis of human plasma demonstrated rapid and extensive met abolism of [C-11]DACA. The levels of [C-11]DACA changed from 77 +/- 8% (SD) at 5 min to 25 +/- 5% at 45 min postinjection, Seven radioactive metabolites were observed in human plasma, and one was identified as [C-11]DACA-N-oxide. Rapid clearance of C-11 radioactivity from rat blo od, plasma, and major organs was observed, The half-life of C-11 radio activity clearance in rat blood between 15 and 90 min was calculated t o be 3.2 h; the levels of [C-11]DACA in rat plasma decreased from 69 /- 3% (SD) at 2 minto 29 +/- 1.5% at 25 min, The number of radioactive metabolites in rat plasma was the same as in human plasma except that the proportions differed, Again, one metabolite was identified as the [C-11]DACA-N-oxide. Analysis of rat tissues showed rapid and extensiv e metabolism in tissues, particularly Liver and kidney; however, [C-11 ]DACA (i.e., the parent compound) was the major radioactive component in the Lung, heart, and brain over 40 min, Positron emission tomograph y scanning using [C-11]DACA in tile rat showed little retention of C-1 1 radioactivity in major organs with rapid excretion via gut and kidne y. The rat data were consistent with animal (mouse and rat) preclinica l data obtained with preexisting techniques with longer-lived isotopes , Labeling of potential anticancer drugs with positron-emitting radion uclides and performing in viva preclinical evaluation at tracer doses in animals and humans prior to Phase I clinical trials provides unique information that could speed up tile assessment of the drug and could potentially assist drug development programs. In this example, there was no unexpected interspecies difference in metabolism of DACA that w ould have alerted us to make a change in the planned phase I study.