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Stereoselective pharmacokinetics of oral felodipine and nitrendipine in healthy subjects: correlation with nifedipine pharmacokinetics

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Summary

The pharmacokinetics of racemic (rac) felodipine, rac-nitrendipine and nifedipine (all given as an oral dose of 20 mg in solution) have been investigated in a randomised cross-over study in 12 healthy male subjects using stereoselective assays. Both felodipine and nitrendipine exhibited stereoselective pharmacokinetics. On average, the AUCs of the active (S)-enantiomers of felodipine and nitrendipine were 139% and 104% higher than those of their optical antipodes, but the elimination half-lives of the enantiomers of each racemate were not different. The AUCs of nifedipine, rac-felodipine, rac-nitrendipine and of their enantiomers were highly correlated (all r>0.83), suggesting closely related rate limiting steps in the in vivo first-pass metabolism of these high-clearance drugs. Stereoselectivity was only a minor contributor to inter-individual variability in the oral pharmacokinetics of these compounds in healthy subjects.

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References

  1. Bäärnhielm C, Sk»nberg I, Borg KO (1984) Cytochrome P-450-dependent oxidation of felodipine, a 1,4-dihydropyridine, to the corresponding pyridine. Xenobiotica 14: 719–726

    Google Scholar 

  2. Böcker RH, Guengerich FP (1986) Oxidation of 4-aryl- and 4-alkyl-substituted 2,6-dimethyl-3,5-bis (alkoxycarbonyl)-1,4-dihydropyridines by human liver microsomes and immunochemical evidence for the involvement of a form of cytochrome P-450. J Med Chem 29: 1596–1603

    Google Scholar 

  3. Böcker RH, Preuss E, Peter R (1990) High-performance liquid chromatography of the metabolites of nitrendipine and investigation into the metabolic pathways of this dihydropyridine. J Chromatogr 530: 206–211

    Google Scholar 

  4. Guengerich FP, Böcker RH (1988) Cytochrome P-450-catalyzed dehydrogenation of 1,4-dihydropyridines. J Biol Chem 263: 8168–8175

    Google Scholar 

  5. Reg»rdh CG, Bäärnhielm C, Edgar B, Hoffmann KJ (1990) Pharmacokinetics and metabolism of 1,4-dihydropyridine calcium antagonists. Prog Drug Metab 12: 41–86

    Google Scholar 

  6. Rush WR, Alexander O, Hall DJ, Cairncross L, Dow RJ, Graham DJG (1986) The metabolism of nicardipine hydrochloride in healthy male volunteers. Xenobiotica 16: 341–349

    Google Scholar 

  7. Scherling D, Karl W (1988) Biotransformation of nimodipine. 11th European Workshop on Drug Metabolism, Konstanz (FRG), 11–16 September 1988, Abstract 3.50

  8. Scherling D, Karl W, Ahr G, Ahr HJ, Wehinger E (1988) Pharmacokinetics of nisoldipine III. Biotransformation of nisoldipine in rat, dog, monkey and man. Arzneim Forsch 38: 1105–1110

    Google Scholar 

  9. Guengerich FP, Martin MV, Beaune PH, Kremers P, Wolff T, Waxman DJ (1986) Characterization of rat and human liver microsomal cytochrome P-450 involved in nifedipine oxidation, a prototype for genetic polymorphism in oxidative drug metabolism. J Biol Chem 261: 5051–5060

    Google Scholar 

  10. Guengerich FP, Brian WR, Iwasaki M, Sari MA, Bäärnhielm C, Berntsson P (1991) Oxidation of dihydropyridine calcium channel blockers and analogues by human liver cytochrome P-450 IIIA4. J Med Chem 34: 1838–1844

    Google Scholar 

  11. Porchet HC, Dayer P (1990) Serum concentrations and effects of (±)-nicardipine compared with nifedipine in a population of healthy subjects. Clin Pharmacol Ther 48: 155–160

    Google Scholar 

  12. Blychert E, Edgar B, Elmfeldt D, Hedner T (1991) A population study of the pharmacokinetics of felodipine. Br J Clin Pharmacol 31: 15–24

    Google Scholar 

  13. Edgar B, Lundborg P, Reg»rdh CG (1987) Clinical pharmacokinetics of felodipine, a summary. Drugs [Suppl 3] 34: 16–27

    Google Scholar 

  14. Kleinbloesem CH, van Brummelen P, Faber H, Danhof M, Vermeulen NPE, Breimer DD (1984) Variability in nifedipine pharmacokinetics and dynamics: a new oxidation polymorphism in man. Biochem Pharmacol 33: 3721–3724

    Google Scholar 

  15. Soons PA, de Boer AG, van Brummelen P, Breimer DD (1989) Oral absorption profile of nitrendipine in healthy subjects: a kinetic and dynamic study. Br J Clin Pharmacol 27: 179–189

    Google Scholar 

  16. Soons PA, Schellens JHM, Breimer DD (1992) Variability in pharmacokinetics and metabolism of nifedipine and other dihydropyridine calcium entry blockers. In: Kalow W (ed) Pharmacogenetics of drug metabolism, Pergamon Press, New York, 769–789

    Google Scholar 

  17. Soons PA, Schellens JHM, Cohen AF, Breimer DD (1989) Inter-and intra-individual variability in nifedipine pharmacokinetics and effects. Eur J Clin Pharmacol 36 [Suppl A]: 68

    Google Scholar 

  18. Challenor VF, Waller DG, Renwick AG, Gruchy BS, George CF (1987) The trans-hepatic extraction of nifedipine. Br J Clin Pharmacol 24: 473–477

    Google Scholar 

  19. Wang SX, Sutfin TA, Bäärnhielm C, Reg»rdh CG (1989) Contribution of the intestine to the first-pass metabolism of felodipine in the rat. J Pharmacol Exp Ther 250: 632–636

    Google Scholar 

  20. Guengerich FP (1989) Characterization of human microsomal cytochrome P-450 enzymes. Ann Rev Pharmacol Toxicol 29: 241–264

    Google Scholar 

  21. Van Harten J, Burggraaf J, Danhof M, van Brummelen P, Breimer DD (1989) The contribution of nisoldipine-induced changes in liver blood flow to its pharmacokinetics after oral administration. Br J Clin Pharmacol 27: 581–586

    Google Scholar 

  22. van Harten J, van Brummelen P, Ooms P, Danhof M, Blauw GJ, Breimer DD (1989) Variability in the pharmacokinetics of nisoldipine as caused by differences in liver blood flow response. J Clin Pharmacol 29: 714–721

    Google Scholar 

  23. Breimer DD, Schellens JHM (1990) A ‘cocktail’ strategy to assess in vivo oxidative drug metabolism in humans. TiPS 11: 223–225

    Google Scholar 

  24. Lobo J, Jack DB, Kendall MJ (1986) The intra- and inter-subject variability of nifedipine pharmacokinetics in young volunteers. Eur J Clin Pharmacol 30: 57–60

    Google Scholar 

  25. Lobo J, Jack DB, Kendall MJ (1987) Inter- and intra-subject variability of nitrendipine and the effect of food. Eur J Clin Pharmacol 32: 357–360

    Google Scholar 

  26. Edgar B, Collste P, Wingstrand K (1988) Intra- and inter-individual variation in plasma concentrations of felodipine-ER (Plendil®) in healthy subjects. Symposium on Variability in Pharmacokinetics and Drug Response, Gothenburg, Sweden, 3–5 October 1988, Abstract 46

  27. Bellemann P, Schade A, Towart R (1983) Dihydropyridine receptor in rat brain labelled with [3H] nimodipine. Proc Natl Acad Sci USA 80: 2356–2360

    Google Scholar 

  28. Eltze M, Boer R, Sanders KH, Boss H, Ulrich WR, Flockerzi D (1990) Stereoselective inhibition of thromboxane-induced coronary vasoconstriction by 1,4-dihydropyridine calcium channel antagonists. Chirality 2: 233–240

    Google Scholar 

  29. Mikus G, Mast V, Ratge D, Wisser H, Eichelbaum M (1989) Pharmacokinetics, hemodynamic and biochemical effects of the nitrendipine enantiomers. Eur J Clin Pharmacol 36 [Suppl A]: 179

    Google Scholar 

  30. Mörike K, Mast V, Mikus G, Ratge D, Wisser H, Eichelbaum M (1989) Hämodynamische und biochemische Wirkungen der Nitrendipin-Enantiomere. Klin Wochenschr 67 [Suppl 16]: 120–121

    Google Scholar 

  31. Soons PA, Roosemalen MCM, Breimer DD (1990) Enantiose-lective determination of felodipine and other chiral dihydropyridine calcium entry blockers in human plasma. J Chromatogr 528: 343–356

    Google Scholar 

  32. Soons PA, Roosemalen MCM, Breimer DD (1991) Stereoselective pharmacokinetics of oral and intravenous nitrendipine in healthy male subjects. Br J Clin Pharmacol 32: 11–16

    Google Scholar 

  33. Soons PA, Breimer DD (1988) Gas chromatographic analysis of nitrendipine and its pyridine metabolite in human plasma. J Chromatogr 428: 362–368

    Google Scholar 

  34. Soons PA, Schellens JHM, Roosemalen MCM, Breimer DD (1991) Analysis of nifedipine and its pyridine metabolite dehydronifedipine in blood and plasma: review and improved high-performance liquid chromatographic methodology. J Pharm Biomed Anal 9: 475–484

    Google Scholar 

  35. Gibaldi M, Perrier D (1982) Pharmacokinetics, 2nd edn. Dekker, New York

    Google Scholar 

  36. Aronson JK, Dengler HJ, Dettli L, Follath F (1988) Standardization of symbols in clinical pharmacology. Eur J Clin Pharmacol 35: 1–7

    Google Scholar 

  37. Niwa T, Tokuma Y, Nakagawa K, Noguchi H, Yamazoe Y, Kato R (1988) Stereoselective oxidation and plasma protein binding of nilvadipine, a new dihydropyridine calcium antagonist, in man. Res Commun Chem Pathol Pharmacol 60: 161–172

    Google Scholar 

  38. Tokuma Y, Fujiwara T, Noguchi H (1987) Plasma levels of (+)-and (−)-nilvadipine after oral dosing with racemic (±)-nilvadipine in man. Res Commun Chem Pathol Pharmacol 57: 229–237

    Google Scholar 

  39. Frost N, Ahr G, Weber H, Kuhlmann J (1990) Nisoldipine enantiomers. Assessment of the pharmacokinetics by stable isotope technique. In: Kuhlmann J, Wingender W (eds) Dose-response relationship of drugs. Zuckschwerdt, München, pp 87–92

    Google Scholar 

  40. Krol GJ, Lettieri JT, Yeh SC, Burkholder DE, Birkett JP (1987) Disposition and pharmacokinetics of 14C-nitrendipine in healthy volunteers. J Cardiovasc Pharmacol 9 [Suppl 4]: 122–128

    Google Scholar 

  41. Mikus G, Fischer C, Heuer B, Langen C, Eichelbaum M (1987) Application of stable isotope methodology to study the pharmacokinetics, bioavailability and metabolism of nitrendipine after i. v. and p. o. administration. Br J Clin Pharmacol 24: 561–569

    Google Scholar 

  42. Sorkin EM, Clissold SP, Brogden RN (1985) Nifedipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy, in ischaemic heart disease, hypertension and related cardiovascular disorders. Drugs 30: 182–274

    Google Scholar 

  43. Ankermann T, Osterkamp U, Santos SR, Kirch W (1989) Elimination and haemodynamic effects of nitrendipine in patients with chronic renal failure. Eur J Clin Pharmacol 36: 433–437

    Google Scholar 

  44. Van Bortel L, Böhm R, Mooij J, Schiffers P, Rahn KH (1989) Pharmacokinetics of nitrendipine in terminal renal failure. Eur J Clin Pharmacol 36: 467–471

    Google Scholar 

  45. Otto J, Lesko LJ (1986) Protein binding of nifedipine. J Pharm Pharmacol 38: 399–400

    Google Scholar 

  46. Rosenkranz H, Schlossmann K, Scholtan W (1974) Die Bindung von 4-(2'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridin-3,5-dicarbonsäuredimethylester (nifedipine) sowie von anderen koronarwirksamen Stoffen an die Eiweißkörper des Serums. Arzneim Forsch 24: 455–466

    Google Scholar 

  47. Rumiantsev DO, Piotrovskii VK, Metelitsa VI, Slastnikova ID, Martsevich SY, Kokurina EV (1989) Serum binding of nidefipine and verapamil in patients with ischaemic heart disease on monotherapy. Br J Clin Pharmacol 28: 357–361

    Google Scholar 

  48. Kleinbloesem CH, van Brummelen P, van Harten J, Danhof M, Breimer DD (1985) Nifedipine: influence of renal function on pharmacokinetic/hemodynamic relationship. Clin Pharmacol Ther 37: 563–574

    Google Scholar 

  49. Van Bortel L, Böhm R, Mooij J, Schiffers P, Rahn KH (1989) Total and free steady-state plasma levels and pharmacokinetics of nifedipine in patients with terminal renal failure. Eur J Clin Pharmacol 37: 185–189

    Google Scholar 

  50. Guengerich FP (1990) Mechanism-based inactivation of human liver microsomal cytochrome P-450 IIIA4 by gestodene. Chem Res Toxicol 3: 363–371

    Google Scholar 

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Author notes

  1. P. A. Soons

    Present address: Department of Clinical Pharmacokinetics, Glaxo Group Research Ltd., Greenford, Middlesex, UK

Authors and Affiliations

  1. Center for Bio-Pharmaceutical Sciences Division of Pharmacology, University of Leiden, Leiden, The Netherlands

    P. A. Soons, T. M. T. Mulders, E. Uchida & D. D. Breimer

  2. Centre for Human Drug Research, Leiden, The Netherlands

    E. Uchida, H. C. Schoemaker & A. F. Cohen

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  1. P. A. Soons
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  2. T. M. T. Mulders
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  5. A. F. Cohen
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  6. D. D. Breimer
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Additional information

Haemodynamic data and pharmacokinetic-pharmacodynamic relationships obtained in this study are reported in the accompanying paper

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Soons, P.A., Mulders, T.M.T., Uchida, E. et al. Stereoselective pharmacokinetics of oral felodipine and nitrendipine in healthy subjects: correlation with nifedipine pharmacokinetics. Eur J Clin Pharmacol 44, 163–169 (1993). https://doi.org/10.1007/BF00315475

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  • DOI: https://doi.org/10.1007/BF00315475

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