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

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).

Oral absorption profile of nitrendipine in healthy subjects: a kinetic and dynamic study.

“…Since nitrendipine exhibits multicompartment kinetics, the estimated elimination half-life is dependent on the time interval after dosing from which the t½, is calculated. When a dose of 20 mg nitrendipine is administered, the assay sensitivity is therefore one of the major causes of the wide variation (3.7-19.9) in mean half-life that have been reported (Aronoff, 1984;Hangson et al, 1984;Kann et al, 1984;Krol et al, 1987a;Lettieri et al, 1987;Mikus et al, 1987;Raemsch & Sommer, 1984 (Lasseter et al, 1984;Raemsch & Sommer, 1984). Bioavailability of the tablet was 11.1 ± 4.5% indicating an extraction ratio of 89% if complete absorption is assumed.…”

“…infusion. The rates of input were normalized to the relative bioavailability of the Osmet, assuming complete absorption for the tablet (Krol et al, 1987a;Mikus et al, 1987;Raemsch & Sommer, 1984 For the tablet, pronounced interindividual differences in the shape of the plasma concentration-time profiles were seen, with large intersubject variability in tmax (0.7-4.7 h) and in Cmax (3.3-27.8 ng ml-1). The plasma concentration-time profiles for the Osmet and for the intravenous infusion exhibited far less intersubject variability.…”

Stereoselective pharmacokinetics of oral and intravenous nitrendipine in healthy male subjects.

“…The marked difference in AUC between enantiomers upon oral administration could theoretically be accounted for partially by differences in the extent of absorption from the intestinal lumen. However, since the absorption of the racemate is at least 80-90% (Krol et al, 1987;Mikus et al, 1987), a difference of only 25-50% could cause such a difference in absorption. In general, absorption from the g.i.…”

“…Most of this variability can be attributed to variable presystemic elimination of the drug since it is much less following intravenous administration, and the absorption from the g.i. tract is almost complete (Krol et al, 1987;Mikus et al, 1987).…”

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

“…Most published data on the pharmacokinetics, bioavailability, metabolism and pharmacological actions of nitrendipine have been based on total plasma drug concentrations not taking account of stereoisomeric composition (Ankermann et al, 1989;Aronoff & Sloan, 1985;Dylewicz et al, 1987;Kann et al, 1984;Kendall et al, 1987;Krol et al, 1987;Lasseter et al, 1984; Lettieri et al, 1987;Mikus et al, 1987;Raemsch et al, 1986;Raemsch & Sommer, 1984;Soons et al, 1989).…”