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Calcium Antagonists

Pharmacokinetic Properties

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Summary

An understanding of the pharmacokinetics of the calcium antagonists (slow-channel blocking drugs) is essential in order to design appropriate dosage regimens which will provide optimum therapeutic efficacy with these agents. This review summarises and evaluates the current state of knowledge of the absorption and disposition characteristics of the 3 most extensively used calcium antagonists in cardiovascular therapeutics: verapamil, diltiazem and nifedipine. While an extensive literature regarding the kinetics of verapamil exists, reports dealing with diltiazem and nifedipine are limited. This is, in part, due to difficulties in developing simple, specific and sensitive analytical procedures.

All 3 drugs undergo extensive metabolism in the liver. Metabolites of verapamil (norverapamil) and diltiazem (desacetyldiltiazem) accumulate in the plasma of patients and have been shown to produce some effects similar to those of their parent compounds.

The bioavailability of diltiazem and nifedipine has not been well studied, and no investigations of the absolute bioavailability of these compounds have been reported. However, the bioavailability of verapamil has been studied extensively; about 22% of an orally administered dose of verapamil is systemically available. Bioavailability is increased when liver function is impaired, such as in patients with hepatic cirrhosis. The high first-pass extraction of verapamil has been suggested to be stereoselective, with preferential elimination of the (−) isomer.

The plasma concentration-time curves of verapamil and diltiazem have been studied following oral administration. The elimination half-lives of verapamil and diltiazem are about 8 and 5 hours, respectively. All 3 drugs are highly protein-bound in the plasma. Several other drugs have the ability to displace verapamil from plasma protein binding sites, but the clinical significance of this interaction is doubtful. Other drug interactions have been investigated with these agents. Verapamil causes digoxin plasma levels to rise during concomitant administration, but no drugs have been shown to alter the disposition of verapamil. Diazepam affects the plasma levels of diltiazem leading to a decrease. The mechanism of this interaction has not been reported, but an effect on bioavailability has been suggested.

Age has been shown to be a factor in the disposition of both diltiazem and verapamil. Older patients tend to have lower clearances of these 2 drugs than do younger patients. It has also been shown that hepatic cirrhosis leads to a decreased clearance of verapamil.

Plasma level monitoring may be helpful for adjusting doses of both verapamil and diltiazem, despite the absence of a definition of therapeutic plasma concentrations. These agents all have low, and highly variable, systemic availability, and plasma concentrations cannot be predicted after oral administration.

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References

  • Chou, R.C. and Levy, G.: Does heparin cause inhibition of drug-protein binding in vivo? Clinical Pharmacology and Therapeutics 29: 236 (1981).

    Google Scholar 

  • Dominic, J.A.; Bourne, D.W.A.; Tan, T.G.; Kirsten, E. and McAllister, R.G.: The pharmacology of verapamil. III. Pharmacokinetics in normal subjects after intravenous drug administration. Journal of Cardiovascular Pharmacology 3: 25–38 (1981).

    Article  PubMed  CAS  Google Scholar 

  • Eichelbaum, M.; Ende, M.; Remberg, G.; Schomerus, M. and Dengler, H.J.: The metabolism of DL-[14C]-verapamil in man. Drug Metabolite Disposition 7: 145–148 (1979).

    CAS  Google Scholar 

  • Eichelbaum, M.; Birkel, P.; Grube, E.; Gutgemann, U. and Somogyi, A.: Effects of verapamil on P-R intervals in relation to verapamil plasma levels following single I.V. and oral administration and during chronic treatment. Klinische Wochenschrift 58: 919–925 (1980a).

    Article  PubMed  CAS  Google Scholar 

  • Eichelbaum, M.; Albrecht, M.; Kliems, G.; Schäfer, K. and Somogyi, A.: Influence of meso-caval shunt surgery on verapamil kinetics, bioavailability and response. British Journal of Clinical Pharmacology 10: 527–529 (1980b).

    Article  PubMed  CAS  Google Scholar 

  • Eichelbaum, M.; Somogyi, A.; von Unruh, G.E. and Dengler, H.J.: Simultaneous determination of the intravenous and oral pharmacokinetic parameters of D,L-verapamil using stable isotope-labelled verapamil. European Journal of Clinical Pharmacology 19: 131–137 (1981).

    Google Scholar 

  • Freedman, S.B.; Richmond, D.R.; Ashley, J.J. and Kelly, D.T.: Verapamil kinetics in normal subjects and patients with coronary artery spasm. Clinical Pharmacology and Therapeutics 30: 644–652 (1981).

    Article  PubMed  CAS  Google Scholar 

  • Harapat, S.R. and Kates, R.E.: High performance liquid Chromatographic analysis of verapamil. II. Simultaneous quantitation of verapamil and its active metabolite, norverapamil. Journal of Chromatography 181: 484–489 (1980).

    Article  PubMed  CAS  Google Scholar 

  • Hege, H.G.: Gas-chromatographic determination of verapamil in plasma and urine. Arzneimittel-Forschung 29: 1681–1684 (1979).

    PubMed  CAS  Google Scholar 

  • Higuchi, S. and Shiobara, Y.: Quantitative determination of nifedipine in human plasma by selected ion monitoring. Biomedical Mass Spectrometry 5: 220–223 (1978).

    Article  PubMed  CAS  Google Scholar 

  • Horster, F.A.: Pharmacokinetics of nifedipine-14C in man; in Lochner (Ed.) 2nd International Adalat Symposium, pp. 124–127 (Springer-Verlag, Berlin 1975).

  • Jakobsen, P.; Lederballe Pedersen, O. and Mikkelsen, E.: Gas Chromatographic determination of nifedipine and one of its metabolites using electron capture detection. Journal of Chromatography: Biomedical Applications 162: 81–87 (1979).

    Article  CAS  Google Scholar 

  • Jaouni, T.M.; Leon, M.B.; Rosing, D.R. and Fales, H.M.: Analysis of verapamil in plasma by liquid chromatography. Journal of Chromatography 182: 473–477 (1980).

    Article  PubMed  CAS  Google Scholar 

  • Kates, R.E.; Keefe, D.L.D.; Schwartz, J.; Harapat, S.; Kirsten, E.B. and Harrison, D.C.: Verapamil disposition kinetics in chronic atrial fibrillation. Clinical Pharmacology and Therapeutics 30: 44–51 (1981).

    Article  PubMed  CAS  Google Scholar 

  • Keefe, D.L.; Yee, Y.G. and Kates, R.E.: Verapamil protein binding in patients and in normal subjects. Clinical Pharmacology and Therapeutics 29: 21–26 (1981).

    Article  PubMed  CAS  Google Scholar 

  • Kinney, E.L.; Moskowitz, R.M. and Zelis, R.: The pharmacokinetics and pharmacology of oral diltiazem in normal volunteers. Journal of Clinical Pharmacology 21: 337–342 (1981).

    PubMed  CAS  Google Scholar 

  • Klein, H.O.; Lang, R.; Weiss, E.; Di Segni, E.; Libhaber, C.; Guerrero, J. and Kaplinsky, E.: The influence of verapamil on serum digoxin concentration. Circulation 65: 998–1003 (1982).

    Article  PubMed  CAS  Google Scholar 

  • Koike, Y.; Shimamura, K.; Shudo, I. and Saito, H.: Pharmacokinetics of verapamil in man. Research Communications in Chemical Pathology and Pharmacology 24: 37–41 (1979).

    PubMed  CAS  Google Scholar 

  • Kuwada, M.; Tateyama, T. and Tsutsumi, J.: Simultaneous determination of verapamil and its seven metabolites by high performance liquid chromatography. Journal of Chromatography: Biomedical Applications 222: 507–511 (1981).

    Article  CAS  Google Scholar 

  • McAllister, R.G. and Howell, S.M.: Fluorimetric assay of verapamil in biological fluids and tissues. Journal of Pharmaceutical Sciences 65: 431–432 (1976).

    Article  PubMed  CAS  Google Scholar 

  • McAllister, R.G.; Tan, T.G. and Bourne, D.W.A.: GLC assay of verapamil in plasma: Identification of fluorescent metabolites after oral drug administration. Journal of Pharmaceutical Sciences 68: 574–577 (1979).

    Article  PubMed  CAS  Google Scholar 

  • Medenwald, V.H.; Schlossmann, K. and Wunsche, C.: Strukturaufklärung der renalen ausscheidungs-produkte von 4-(2′-nitrophenyl)-2,6-dimethyl-l,4-dihydropyridine-3,5-dicarbon-säuredemethylester. Arzneimittel-Forschung 22: 53–56 (1972).

    PubMed  CAS  Google Scholar 

  • Morselli, P.L.; Rovei, V.; Mitchard, M.; Durand, A.; Gomeni, R. and Larribaud, J.: 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, pp. 152–168 (Excerpta Medica, Amsterdam Princeton 1979).

    Google Scholar 

  • Naranjo, C.A.; Sellers, E.M.; Khouw, V.; Alexander, P.; Fan, T. and Shaw, J.: Variability in heparin effect on serum drug bindings. Clinical Pharmacology and Therapeutics 28: 545–550 (1980).

    Article  PubMed  CAS  Google Scholar 

  • Nelson, K.; Woodcock, B.G. and Kirsten, R.: Improvement of the quantiative determination of verapamil in human plasma. International Journal of Clinical Pharmacology and Biopharmacy 17: 375–379 (1979).

    PubMed  CAS  Google Scholar 

  • Neugebauer, G.: Comparative cardiovascular actions of verapamil and its major metabolites in the anaesthetised dog. Cardiovascular Research 12: 247–254 (1978).

    Article  PubMed  CAS  Google Scholar 

  • Pedersen, K.E.; Dorph-Pedersen, A.; Hvidt, S.; Klitgaard, N.A. and Pedersen, K.K.: The long-term effect of verapamil on plasma digoxin concentration and renal digoxin clearance in healthy subjects. European Journal of Clinical Pharmacology 22: 123–127 (1982).

    Article  PubMed  CAS  Google Scholar 

  • Rovei, V.; Mitchard, M. and Morselli, P.L.: Simple, sensitive and specific gas Chromatographic method for the quantification of diltiazem in human body fluids. Journal of Chromatography 138: 391–398 (1977).

    Article  CAS  Google Scholar 

  • Rovei, V.; Gomeni, R.; Mitchard, M.; Larribaud, J.; Blatrix, C.; Thebault, J.J. and Morselli, P.L.: Pharmacokinetics and metabolism of diltiazem in man. Acta Cardiologica 35: 35–45 (1980).

    PubMed  CAS  Google Scholar 

  • Schlossmann, K.; Medenwald, H. and Rosen Kranz, H.: Investigations on the metabolism and protein binding of nifedipine; in Lochner (Ed.) 2nd International Adalat Symposium, pp.33–39 (Springer-Verlag, Berlin 1975).

    Chapter  Google Scholar 

  • Schomerus, M.; Spiegelhalder, B.; Stieren, B. and Eichelbaum, M.: Physiological disposition of verapamil in man. Cardiovascular Research 10: 605–612 (1976).

    Article  PubMed  CAS  Google Scholar 

  • Schwartz, J.B.; Keefe, D.; Kates, R.E.; Kirsten, E. and Harrison, D.C.: Acute and chronic pharmacodynamic interaction of verapamil and digoxin in atrial fibrillation. Circulation 65: 1163–1170 (1982).

    Article  PubMed  CAS  Google Scholar 

  • Shand, D.G.; Hammil, S.C.; Aanonsen, L. and Pritchett, E.L.C.: Reduced verapamil clearance during long-term oral administration. Clinical Pharmacology and Therapeutics 30: 701–703 (1981).

    Article  PubMed  CAS  Google Scholar 

  • Somogyi, A.; Albrecht, M.; Kliems, G.; Schäfer, K. and Eichelbaum, M.: Pharmacokinetics, bioavailability and ECG response of verapamil in patients with liver cirrhosis. British Journal of Clinical Pharmacology 12: 51–60 (1981).

    Article  PubMed  CAS  Google Scholar 

  • Spiegelholder, B. and Eichelbaum, M.: Determination of verapamil in human plasma by mass fragmentography using stable isotope labelled verapamil as internal standard. Arzneimittel-Forschung (Drug Research) 27: 94–97 (1977).

    Google Scholar 

  • Woodcock, B.G.; Hopf, R. and Kalterbach, M.: Verapamil and norverapamil plasma concentrations during long-term therapy in patients with hypertrophic obstructive cardiomyopathy. Journal of Cardiovascular Pharmacology 2: 17–23 (1980).

    Article  PubMed  CAS  Google Scholar 

  • Yong, C.L.; Kunka, R.L. and Bates, T.R.: Factors affecting the plasma protein binding of verapamil and norverapamil in man. Research Communications in Chemical Pathology and Pharmacology 30: 329–339 (1980).

    PubMed  CAS  Google Scholar 

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  1. Cardiology Division, Stanford University Medical Center, Stanford, California, 94305, USA

    Robert E. Kates

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Kates, R.E. Calcium Antagonists. Drugs 25, 113–124 (1983). https://doi.org/10.2165/00003495-198325020-00002

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