Application of stable isotope methodology to study the pharmacokinetics, bioavailability and metabolism of nitrendipine after i.v. and p.o. administration.

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-1 kg-1 and volume of distribution at steady state 5.4 +/- 2.4 1 kg-1. 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).