Gas chromatography-mass spectrometry of perindopril and its active free metabolite, an angiotensin convertase inhibitor: choice of derivatives and ionization modes.

Perindopril, a perhydroindole compound and a novel class of angiotensin convertase inhibitor, after oral administration leads to an active metabolite by de-esterification of an ethyl ester. Routine biological measurements are currently done using a radioimmunological assay, but a mass fragmentographic method was developed using plasma spiked with the drugs, which were then derivatized to the isobutyl ester heptofluorobutyramide and assayed using ammonia negative chemical ionization. Levels of 100 pg/ml were assayed. However, isobutanol derivatization provoked partial transesterification of the ethyl ester of the parent drug into the diisobutyl ester derivative, which corresponds to the active metabolite. A second method of derivatization to stable trimethylsilyl esters preserved the original ethyl ester of the parent drug. Despite the lower ionization yields, the mass fragmentographic method was sensitive and accurate enough to work satisfactorily at the 2 ng/ml level in spiked plasma, which is the level found currently in patients.