No abstract

1 The pharmacokinetics, bioavailability and metabolism of nitrendipine were studied in six healthy volunteers (three females, three males) using [13C4]-nitrendipine as a biological internal standard. In the first study the drug was administered simultaneously by the i.v.[13C4] and p.o. (solution) routes and in a second study two oral preparations (13C4-solution and commercial tablet) were administered, also simultaneously. 2 The mean terminal elimination half-life was 8.3 ± 3.2 h (range 3.4 to 16 h) with no differences between the intravenous and oral route of administration. Total plasma clearance averaged 18.7 ± 0.6 ml min' kg-' and volume of distribution at steady state 5.4 + 2.4 1kg-. 3 Following oral administration of nitrendipine solution the percentage of dose absorbed was 88.4 ± 16.0% based on urinary excretion of metabolites. Despite its almost complete absorption, absolute bioavailability of the solution was only 22.6 ± 6.7% due to extensive presystemic elimination. The bioavailability of the commercial tablet relative to the solution was 82.2 ± 20.3%. 4 Both after i.v. and oral administration the drug was extensively metabolized with less than 0.5% of the dose excreted as unchanged drug in urine. Cleavage of the two ester functions in position 3 and 5, respectively, to carboxylic acids and further hydroxylation of the methyl groups in position 2 and 6 of the pyridine ring to the corresponding hydroxymethyl carboxylic acids constituted the major urinary metabolites accounting for 35.0 ± 16.5% (i.v.) and 32.8 ± 20.4% (p.o.), respectively, of the dose administered. 5 Binding of nitrendipine to plasma proteins was high with a fraction unbound of only 0.02 ± 0.012 (range 0.011 to 0.036).

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.