CLINICAL ANALYSIS OF SAMPATRILAT, A COMBINED RENAL ENDOPEPTIDASE AND ANGIOTENSIN-CONVERTING ENZYME-INHIBITOR - I - ASSAY IN PLASMA OF HUMANVOLUNTEERS BY ATMOSPHERIC-PRESSURE IONIZATION MASS-SPECTROMETRY FOLLOWING DERIVATIZATION WITH BF3-METHANOL

Sampatrilat is a dual inhibitor of angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) under development for the treatment o f hypertension and congestive heart failure. In order to support the e arly clinical development (with oral administration and an expected lo w bioavailability), a sensitive and selective assay was required. A me thod for plasma was developed and validated employing HPLC-APCI-MS-MS. The plasma samples were extracted on solid-phase extraction cartridge s, derivatised with BF3-methanol, diluted, extracted again and then su bjected to HPLC-APCI-MS-MS. Derivatisation was necessary because the t wo carboxyl group in the molecule prevented efficient ionisation in th e heated nebuliser source. The calibration range was from 0.5 to 20 ng ml(-1) and the lower limit of quantification was 0.5 ng ml(-1). Impre cision and inaccuracy were determined on three separate occasions at t hree concentrations (0.5, 5 and 20 ng ml(-1)) and shown to be lower th an 10% in every case. (C) 1998 Elsevier Science B.V.