After administration of a mixed dose of both radioisotope and stable-isotope-labeled tirilazad, we carried out a parallel set of HPLC analyses for drug metabolites in bile samples from monkeys and dogs using either radioactivity monitoring (RAM) for 14C or the chemical reaction interface mass spectrometry technique (CRIMS) to detect 13C or 15N. CRIMS is a novel method where analytes are decomposed in a microwave-induced plasma and the elements contained in the analytes are reformulated into small gaseous species that are detected by a mass spectrometer. The comprehensiveness of detection, chromatographic resolution, sensitivity, signal/noise, and quantitative abilities of CRIMS were compared with RAM and in no case was RAM superior. This implies that stable isotopes may be substituted for radioisotopes in studies of drug metabolism where the ability of the latter approach to detect a label independent of the structures in which the label appears has been the primary reason for continuing to use a hazardous and expensive tracer. With HPLC-CRIMS, stable isotopes such as 13C and 15N can be comprehensively detected and quantitative patterns of drug metabolism from biological fluids can be produced that mirror the results when 14C is used.