Quantification of nitrendipine by stable isotope dilution and electron-capture negative ion chemical ionization

Abstract

The electron-capture properties of nitrendipine, a 1,4-dihydro-pyridine derivative with antihypertensive activity, have been applied to develop a sensitive and specific assay in biological fluids using capillary column gas chromatography and measurement in negative ion chemical ionization mode. The synthesis of a 13C4-labelled analogue suitable as a biological internal standard for bioavailability studies and of a 2H8-labelled analogue, which serves as internal standard, is described. The electron-capture positive ion chemical ionization and electron-capture negative ion chemical ionization mass spectra of nitrendipine and its isotope-labelled analogues are compared. The assay has a detection limit of 100 pg ml-1 plasma with a coefficient of variation of 10.2% using the selected ion monitoring mode and electron-capture negative ion chemical ionization. The method is specific, sensitive and accurate to determine terminal half-life times after intravenous and oral administration of nitrendipine and its 13C-analogue. From the nearly identical plasma concentration-time profile of nitrendipine and its 13C-labelled analogue, an isotopic effect can be excluded. Thus, the synthesized 13C4-analogue should be well suited as a biological standard for bioavailability studies.

Pharmacokinetics, bioavailability, metabolism and acute and chronic antihypertensive effects of nitrendipine in patients with chronic renal failure and moderate to severe hypertension.

“…After the purpose of the study was explained all patients gave written consent to participate in the study which was approved by the local Ethics committee. A complete physical examination and appropriate laboratory tests were performed before the (Fischer et al, 1986). This method is specific and has a limit of detection of 0.05 ng ml-1.…”

Use of pseudoracemic nitrendipine to elucidate the metabolic steps responsible for stereoselective disposition of nitrendipine enantiomers.

“…Nitrendipine and (13C4)-nitrendipine in serum were measured by GC/MS (selected ion monitoring of the molecular ion in negative ion chemical ionization mode) using racemic [2H8]-nitrendipine as internal standard (Fischer et al, 1986). The isotope content of the deuterated internal standard was 99.8%.…”

Lack of effect of nitrendipine on the pharmacokinetics and pharmacodynamics of midazolam during steady state.

“…Serum concentrations of nitrendipine were determined by a specific GC-MS method with minor modifications as recently described (Fischer et al, 1986; during extraction procedure the charcoal purification step was omitted and a 1:1 mixture of ethylacetate/ hexane was used as extraction solvent).…”