Biotransformation studies of di-acid angiotensin converting enzyme inhibitors

The biotransformation of di-acid angiotensin converting enzyme inhibitors (I) to cyclized lactam metabolites was studied in the urine of rats using gas chromatography-mass spectrometry. Chemical synthesis of the corresponding piperazine-dione metabolite (III) was achieved by reaction of enalapril, perindopril or ramipril with acetic acid anhydride followed by hydrolysis of the ester group by sodium in ethanol or by acid hydrolysis. Electron impact and chemical ionization mass spectra confirmed the structure of these potential novel metabolites. Selected ion monitoring of urinary extracts demonstrated small amounts (less than 5%) of these lactams for all three inhibitors, however, it was shown that the majority of these lactams were formed as a result of sample treatment rather than due to biotransformation.