Simultaneous determination of the prodrug zofenopril and its active drug in plasma by capillary gas chromatography-mass-selective detection.

After oral administration of zofenopril, the active sulfhydryl angiotensin-converting enzyme inhibitor is released. Zofenopril is currently under clinical investigation as an antihypertensive. Blood samples are reacted with N-ethylmaleimide, immediately after collection, processed into plasma and stored frozen for subsequent analysis. After addition of two internal reference standards, one each for the prodrug and the active compound, the plasma samples are purified by a combination of liquid-liquid and solid-phase extractions. The dried methylated extracts are reconstituted with tetramethylbenzene and chromatographed by automated splitless injection on a fused-silica capillary column, connected to a mass-selective detector. The analytes and the internal reference standards are chromatographically resolved and a common fragment ion is monitored for the analytes. A limit of quantitation of approximately 1 ng/ml of plasma is achieved.