REPLACING C-14 WITH STABLE ISOTOPES IN DRUG-METABOLISM STUDIES

After administration of a mixed dose of both radioisotope and stable-i sotope-labeled tirilazad, we carried out a parallel set of HPLC analys es for drug metabolites in bile samples from monkeys and dogs using ei ther radioactivity monitoring (RAM) for C-14 or the chemical reaction interface mass spectrometry technique (CRIMS) to detect C-13 or N-15. CRIMS is a novel method where analytes are decomposed in a microwave-i nduced plasma and the elements contained in the analytes are reformula ted into small gaseous species that are detected by a mass spectromete r. The comprehensiveness of detection, chromatographic resolution, sen sitivity, signal/noise, and quantitative abilities of CRIMS were compa red with RAM and in no case was RAM superior. This implies that stable isotopes may be substituted for radioisotopes in studies of drug meta bolism where the ability of the latter approach to detect a label inde pendent of the structures in which the label appears has been the prim ary reason for continuing to use a hazardous and expensive tracer. Wit h HPLC-CRIMS, stable isotopes such as C-13 and N-15 can be comprehensi vely detected and quantitative patterns of drug metabolism from biolog ical fluids can be produced that mirror the results when C-14 is used.