Clinical analysis of sampatrilat, a combined renal endopeptidase and angiotensin-converting enzyme inhibitor I: assay in plasma of human volunteers by atmospheric-pressure ionisation mass-spectrometry following derivatisation with BF3-methanol.
Sampatrilat is a dual inhibitor of angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) under development for the treatment of hypertension and congestive heart failure. In order to support the early clinical development (with oral administration and an expected low bioavailability), a sensitive and selective assay was required. A method for plasma was developed and validated employing HPLC APCI MS-MS. The plasma samples were extracted on solid-phase extraction cartridges, derivatised with BF3-methanol, diluted, extracted again and then subjected to HPLC APCI-MS-MS. Derivatisation was necessary because the two carboxyl group in the molecule prevented efficient ionisation in the 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). Imprecision and inaccuracy were determined on three separate occasions at three concentrations (0.5, 5 and 20 ng ml[-1]) and shown to be lower than 10% in every case.
Venn
R F
RF
Department of Drug Metabolism, Pfizer Central Research, Sandwich, Kent, UK. richard_venn@sandwich.pfizer.com
Kaye
B
B
Macrae
P V
PV
Saunders
K C
KC
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000097:blood* / Q000493:pharmacokinetics; D001682:Biological Availability; D010450:Endopeptidases / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000201:enzymology*; D013058:Mass Spectrometry / Q000379:methods*; D008698:Mesylates / Q000097:blood* / Q000493:pharmacokinetics; D000432:Methanol / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000097:blood* / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics
D000806:Angiotensin-Converting Enzyme Inhibitors; D008698:Mesylates; D011480:Protease Inhibitors; D014443:Tyrosine; D010450:Endopeptidases; C111998:sampatrilat; D000432:Methanol