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-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).
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- Eichelbaum M., Dengler H. J., Somogyi A., von Unruh G. E. Superiority of stable isotope techniques in the assessment of the bioavailability of drugs undergoing extensive first pass elimination. Studies of the relative bioavailability of verapamil tablets. Eur J Clin Pharmacol. 1981 Jan;19(2):127–131. doi: 10.1007/BF00568399. [DOI] [PubMed] [Google Scholar]
- Eichelbaum M., Somogyi A. Inter- and intra-subject variation in the first-pass elimination of highly cleared drugs during chronic dosing. Studies with deuterated verapamil. Eur J Clin Pharmacol. 1984;26(1):47–53. doi: 10.1007/BF00546708. [DOI] [PubMed] [Google Scholar]
- Eichelbaum M., von Unruh G. E., Somogyi A. Application of stable labelled drugs in clinical pharmacokinetic investigations. Clin Pharmacokinet. 1982 Nov-Dec;7(6):490–507. doi: 10.2165/00003088-198207060-00002. [DOI] [PubMed] [Google Scholar]
- Fischer C., Heuer B., Heuck K., Eichelbaum M. Quantification of nitrendipine by stable isotope dilution and electron-capture negative ion chemical ionization. Biomed Environ Mass Spectrom. 1986 Dec;13(12):645–650. doi: 10.1002/bms.1200131202. [DOI] [PubMed] [Google Scholar]
- Heck H. A., Buttrill S. E., Jr, Flynn N. W., Dyer R. L., Anbar M., Cairns T., Dighe S., Cabana B. E. Bioavailability of imipramine tablets relative to a stable isotope-labeled internal standard: increasing the power of bioavailability tests. J Pharmacokinet Biopharm. 1979 Jun;7(3):233–248. doi: 10.1007/BF01060015. [DOI] [PubMed] [Google Scholar]
- Kann J., Krol G. J., Raemsch K. D., Burkholder D. E., Levitt M. J. Bioequivalence and metabolism of nitrendipine administered orally to healthy volunteers. J Cardiovasc Pharmacol. 1984;6 (Suppl 7):S968–S973. [PubMed] [Google Scholar]
- Kazda S., Garthoff B., Luckhaus G. Mode of antihypertensive action of nitrendipine. J Cardiovasc Pharmacol. 1984;6 (Suppl 7):S956–S962. [PubMed] [Google Scholar]
- Lasseter K. C., Shamblen E. C., Murdoch A. A., Burkholder D. E., Krol G. J., Taylor R. J., Jr, Vanov S. K. Steady-state pharmacokinetics of nitrendipine in hepatic insufficiency. J Cardiovasc Pharmacol. 1984;6 (Suppl 7):S977–S981. [PubMed] [Google Scholar]
- Peck C. C., Barrett B. B. Nonlinear least-squares regression programs for microcomputers. J Pharmacokinet Biopharm. 1979 Oct;7(5):537–541. doi: 10.1007/BF01062394. [DOI] [PubMed] [Google Scholar]
- Wagner J. G. Linear pharmacokinetic equations allowing direct calculation of many needed pharmacokinetic parameters from the coefficients and exponents of polyexponential equations which have been fitted to the data. J Pharmacokinet Biopharm. 1976 Oct;4(5):443–467. doi: 10.1007/BF01062831. [DOI] [PubMed] [Google Scholar]