Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Chronopharmacokinetics of Diltiazem

  • 5 Accesses

  • 1 Citations


The chronopharmacokinetics of diltiazem were investigated after administration of a 60mg oral dose (immediate release capsule) at 4 different times over 24 hours (0600, 1200, 1800 and 2400h) to 8 healthy human volunteers in a randomised crossover study with a washout period of 1 week. Serum samples were analysed for unchanged diltiazem using high performance liquid chromatography. Pharmacokinetic parameters were calculated using model independent methods. A significant decrease in the Cmax (F = 6.52, p < 0.002) and AUC0-α (F = 3.26, p < 0.05) as well as an increase in the oral clearance (F = 3.62, p < 0.05) and apparent volume of distribution (F = 5.85, p < 0.01) were observed following administration at 0600h. Following the 2400h dose administration, the elimination half-life was significantly decreased as compared with that at the other dose times (F = 4.11, p < 0.025). These variations appear to be a result of time-dependent changes in the metabolism of diltiazem.

This is a preview of subscription content, log in to check access.


  1. Bertault-Peres P, Bonfils C, Fabre G, Just S, Cano JP, et al. Metabolism of cyclosporine A.II. Implication of macrolide antibiotic inducible cytochrome P-450 3C from rabbit liver microsomes. Drug Metabolism and Disposition 15: 391–398, 1987

  2. Bloedow DG, Piepho RW, Nies AS, Gal J. Serum binding of diltiazem in humans. Journal of Clinical Pharmacology 22: 201–205, 1982

  3. Bruguerolle B, Levi F, Arnaud C, Bouvenot G, Mechkouri M, et al. Alteration in physiological circadian time structure of six plasma proteins in patients with advanced cancer. Annual Review of Chronopharmacology 3: 207–210, 1986

  4. Cal JC, Dorian C, Camber J. Circadian and circannual changes in nephrotoxic effects of heavy metals and antibiotics. Annual Review of Chronopharmacology 2: 143–176, 1985

  5. Canafax DM, Cipolle RJ, Hrushesky JM, Rabatin JT, Min DI, et al. Increased evening exposure to cyclosporine and metabolites. Annual Review of Chronopharmacology 5: 5–8, 1988

  6. Chaffman M, Brogden RN. Diltiazem: a review of its pharmacological properties and therapeutic efficacy. Drugs 29: 387–454, 1985

  7. Combalbert J, Fabre I, Fabre G, Dilet I, Derancourt J, et al. Metabolism of cyclosporin A. IV. Purification and identification of the rifampicin-inducible human liver cytochrome P-450 (cyclosporin-oxidase) as a product of P-450 III A gene subfamily. Drug Metabolism and Disposition 17: 197–207, 1989

  8. Distelrath L, Guengerich FP. Enzymology of human liver cytochrome P-450. In Guengerich (Ed.) Mammalian cytochrome P-450, Vol. 1, pp. 133–198, 1988

  9. Eldon MA, Battle MM, Voigtman RE, Colbum WA. Differences in oral verapamil absorption as a function of time of day. Journal of Clinical Pharmacology 29: 989–993, 1989

  10. Feuers RJ, Scheving LE. Chronobiology of hepatic enzymes. Annual Review of Chronopharmacology 4: 209–256, 1988

  11. Fujimura A, Ohashi K, Sugimoto K, Kumagai Y, Ebihara A. Chronopharmacological study of nitrendipine in healthy subjects. Journal of Clinical Pharmacology 29: 909–915, 1989

  12. Gibaldi M, Perrier D. Pharmacokinetics, 2nd ed., Marcel Dekker, New York, 1982

  13. Guengerich FP, Martin MV, Beaune PH, Cremers P, Wolff T, et al. Characterisation of rat and human liver microsomal cytochrome P-450 forms involved in nifedipine oxidation, a prototype for genetic polymorphism in oxidative drug metabolism. Journal of Biological Chemistry 261: 5051–5060, 1986

  14. Hermann P, Rodger SD, Remones G, Thenot JP, London DR, et al. Pharmacokinetics of diltiazem after intravenous and oral administration. European Journal of Clinical Pharmacology 24: 349–352, 1983

  15. Hla KK, Henry JA, Latham AN. Pharmacokinetics and pharmacodynamics of two formulations of verapamil. British Journal of Clinical Pharmacology 24: 661–664, 1987

  16. Holt DW, Eastwood R, Walker S, Hla KK, Henry JA. Effect of dose time on the pharmacokinetics of nicardipine. European Journal of Pharmacology 183: 1595–1596, 1990

  17. Jesperson CM, Frederiksen M, Hansen JF, Klitgaard NA, Sorum C. Circadian variation in the pharmacokinetics of verapamil. European Journal of Clinical Pharmacology 37: 613–615, 1989

  18. Kelly JG, Devane JG, Geoghegan B. Pharmacokinetic properties and antihypertensive efficacy of once daily diltiazem. Journal of Cardiovascular Pharmacology 17: 957–963, 1991

  19. Kelly JG, O’Malley K. Clinical pharmacokinetics of calcium antagonists, an update. Clinical Pharmacokinetics 22: 416–433, 1992

  20. Koopman MG, Koomen GC, Krediet RT, de Moor EA, Hoek FJ, et al. Circadian rhythm of glomerular filtration rate in normal individuals. Clinical Sciences 77: 105–111, 1989

  21. Lemmer B, Nold G, Behne S, Kaiser R. Chronopharmacology and chronopharmacokinetics of nifedipine. Chronobiology International 8: 485–494, 1991

  22. Montamat SC, Abernethy DR. N-monodesmethyldiltiazem is the predominant metabolite of diltiazem in the plasma of young and elderly hypertensives. British Journal of Clinical Pharmacology 24: 185–189, 1987

  23. Morselli PL, Rovei M, Mitchard M, Durand A, Gomeni R, et al. Pharmacokinetics and metabolism of diltiazem in man (Observations on healthy volunteers and angina pectoris patients). In Bing (Ed.) New drug therapy with a calcium antagonist. Diltiazem hakone Symposium, pp. 152–168, Excerpta Medica, Amsterdam, 1979

  24. Mulcahy D, Cunningham D, Crean P, et al. Circadian variation of total ischemic burden and its alteration with anti-anginal agents. Lancet 1: 755–759, 1988

  25. Muller JE, Stone PH, Turi ZG, et al. Circadian variation in the frequency of onset of acute myocardial infarction. New England Journal of Medicine 313: 1315–1322, 1988

  26. Pichard L, Gillet G, Fabre I, Dalet-Beluche I, Bonfils C, et al. Identification of the rabbit and human cytochromes P-450 III A as major enzymes involved in the N-demethylation of diltiazem. Drug Metabolism and Disposition 18: 711–719, 1990

  27. Pozet N, Brazier JL, Aissa AH, Khenfer D, Faucon G, et al. Pharmacokinetics of diltiazem in severe renal failure. European Journal of Clinical Pharmacology 24: 635–638, 1983

  28. Reinberg A, Levi F, Smolensky MH, Labrecque G, Ollangnier M, et al. In Hansch et al. (Eds) Comprehensive Medicinal Chemistry, Biopharmaceutics, Vol. 5, pp. 279–295. Pergamon Press, Britain, 1990

  29. Ritschel WA. AUC — RPP: Basic computer programme for compartment model independent pharmacokinetic analysis. Methods and Findings in Experimental and Clinical Pharmacology 8: 633–640, 1986

  30. Shively CA, Simons RJ, Passananti GT, Dvorchick BH, Vesell ES. Dietary patterns and diurnal variations in aminopyrine disposition. Clinical Pharmacology and Therapeutics 29: 65–73, 1981

  31. Sugihara J, Sugawara Y, Ando H, Harogaya S, Etoh A, et al. Studies on the metabolism of diltiazem in man. Journal of Pharmacology and Dynamics 7: 24–32, 1984

  32. Wiens RE, Runser DJ, Lacz JP, Dimmitt DC. Quantitation of diltiazem and desacetyldiltiazem in dog plasma by HPLC. Journal of Pharmaceutical Sciences 73: 688–689, 1984

Download references

Author information

Correspondence to Prof. D. Rambhau.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Rao, V.V.S., Rambhau, D. Chronopharmacokinetics of Diltiazem. Drug Invest 6, 10–15 (1993). https://doi.org/10.1007/BF03259420

Download citation


  • High Performance Liquid Chromatography
  • Diltiazem
  • Calcium Antagonist
  • Nicardipine
  • Drug Invest