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Clinical Pharmacokinetics of Calcium Antagonists

An Update

  • Review Article
  • Drug Disposition
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Summary

The calcium antagonists are valuable and widely used agents in the management of essential hypertension and angina. There is an increasing number of new agents to add to the 3 prototype substances nifedipine, diltiazem and verapamil. These new agents are dihydropyridines structurally related to nifedipine. However, they tend to have longer elimination half-lives (t½β) and may be suitable for twice-daily administration. Amlodipine is an exception with a t½β in excess of 30h. Apart from elimination rates, however, the pharmacokinetic characteristics of the newer agents have a notable tendency to resemble those of the established agents. They are highly cleared drugs, are relatively highly protein bound. As they are subject to significant first-pass metabolism, old age and hepatic impairment will increase their plasma concentrations due to a reduced first-pass effect. Renal impairment does little to their pharmacokinetics since the fraction eliminated unchanged by the kidney is small. For most agents, plasma concentration-response relationships have been described. Interesting areas for further research include chronopharmacokinetics, stereoselective pharmacokinetics and lipid solubility. Drugs affecting hepatic blood flow and drug metabolising capacity have predictable interaction potential. Some of the newer calcium antagonists will, like verapamil, increase plasma digoxin concentrations. Verapamil and diltiazem decrease phenazone (antipyrine) metabolism and therefore tend to decrease the metabolism of other drugs.

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References

  • Abernethy DR, Gutkowska J, Winterbottom LM. Effects of amlodipine, a long acting dihydropyridine calcium antagonist in ageing hypertension: pharmacodynamics in relation to disposition. Clinical Pharmacology and Therapeutics 48: 76–86, 1990

    PubMed  CAS  Google Scholar 

  • Abernethy DR, Schwartz JB. Pharmacokinetics of calcium antagonists under development. Clinical Pharmacokinetics 15: 1–14, 1988

    PubMed  CAS  Google Scholar 

  • Abernethy DR, Schwartz JB, Todd EL. Diltiazem and desacetyldiltiazem analysis in human plasma using high performance liquid chromatography: improved sensitivity without derivatization. Journal of Chromatography 342: 216–220, 1985

    PubMed  CAS  Google Scholar 

  • Abernethy DR, Schwartz JB, Todd EL, Luchi R, Snow E. Verapamil pharmacodynamics and disposition in young and elderly hypertensive patients. Annals of Internal Medicine 105: 329–336, 1986

    PubMed  CAS  Google Scholar 

  • Ahmed JH, Grant AC, Rodger RSC, Murray GR, Elliot HL. Inhibitory effect of uraemia on the hepatic clearance and metabolism of nicardipine. British Journal of Clinical Pharmacology 32: 57–62, 1991

    PubMed  CAS  Google Scholar 

  • Ahr G, Wingender W, Kuhlmann J. Pharmacokinetics of nisoldipine. In Hugenholtz & Meyer (Eds) Nisoldipine, pp. 59–66, Springer-Verlag, Heidelberg, 1987

    Google Scholar 

  • Ahsan CH, Renwick AG, Macklin B, Challenor VF, Waller DG, et al. Ethnic differences in the pharmacokinetics of oral nifedipine. British Journal of Clinical Pharmacology 31: 399–403, 1991

    PubMed  CAS  Google Scholar 

  • Anhoff M. Determination of felodipine in plasma by gas chromatography with electron-capture detection. Journal of Pharmaceutical and Biomedical Analysis 2: 519–526, 1984

    Google Scholar 

  • Ankermann T, Osterkampil, Santos SR, Kirch W. Elimination and haemodynamic effects of nitrendipine in patients with chronic renal failure. European Journal of Clinical Pharmacology 36: 433–437, 1989

    PubMed  CAS  Google Scholar 

  • Aoki K, Sato K, Kawaguci Y, Yamamoto M. Acute and long-term hypotensive effects and plasma concentrations of nifedipine in patients with essential hypertension. European Journal of Clinical Pharmacology 23: 197–201, 1982

    PubMed  CAS  Google Scholar 

  • Aronoff GR. Pharmacokinetics of nitrendipine in patients with renal failure: comparison to normal subjects. Journal of Cardiovascular Pharmacology 6 (Suppl. 7): S974–S976, 1984

    PubMed  CAS  Google Scholar 

  • Au TLS, Curtis NJ, Nalker MJA. Effects of (−), (+) and (±) verapamil on coronary occlusion-induced mortality and infarct size. Journal of Cardiovascular Pharmacology 10: 327–331, 1987

    PubMed  CAS  Google Scholar 

  • Bach D, Blevims R, Kerner N, Rubenfire M, Edwards DJ. The effect of verapamil on antipyrine pharmacokinetics and metabolism in man. British Journal of Clinical Pharmacology 21: 655–659, 1986

    PubMed  CAS  Google Scholar 

  • Baksi AK, Edwards JS, Ahr G. A comparison of the pharmacokinetics of nisoldipine in elderly and young subjects. British Journal of Clinical Pharmacology 31: 367–370, 1991

    PubMed  CAS  Google Scholar 

  • Bauer LA, Stenwall M, Horn JR, Davis R, Opheim K, et al. Changes in antipyrine and indocyanine green kinetics during nifedipine, verapamil and diltiazem therapy. Clinical Pharmacology and Therapeutics 40: 239–242, 1986

    PubMed  CAS  Google Scholar 

  • Bell JA, Gower AJ, Martin LE, Mills ENC, Smith WP. Interaction of H2-receptor antagonists with drug-metabolising enzymes. Biochemical Society Transactions 9: 113–114, 1981

    PubMed  CAS  Google Scholar 

  • Beresford AP, Macrae PV, Stopher DA, Wood BA. Analysis of amlodipine in human plasma by gas chromatography. Journal of Chromatography 420: 178–183, 1987

    PubMed  CAS  Google Scholar 

  • Blychert E, Edgar B, Elmfeldt D, Hednert A. A population study of the pharmacokinetics of felodipine. British Journal of Clinical Pharmacology 31: 15–24, 1991

    PubMed  CAS  Google Scholar 

  • Blychert E, Edgar B, Elmfeldt D, Shapiro D. Plasma concentration vs effect relationship for felodipine. Journal of Cardiovascular Pharmacology 15 (Suppl. 4): S57, 1990

    PubMed  Google Scholar 

  • Boelaert J, Valcke Y, Dammekens H, De Vriese G, Ahr G, et al. Pharmacokinetics of nisoldipine in renal dysfunction. European Journal of Clinical Pharmacology 34: 207–209, 1988

    PubMed  CAS  Google Scholar 

  • Bogaert MG, Rosseel MT, Joos R, Boelaert J. Plasma concentrations of nifedipine in patients with renal failure. Arzneimittel-Forschung 34: 307–308, 1984

    PubMed  CAS  Google Scholar 

  • Bossini A, Di Veroli C, Cavallotti G, Cagli V. Felodipine ER formulation in the treatment of mild hypertension: efficacy and tolerability vs placebo. British Journal of Clinical Pharmacology 30: 56–571, 1990

    Google Scholar 

  • Breimer DD, Lodewijks MThM, Van Brummelen P, Van Harten J, Wilson JPH. Pharmacokinetics and haemodynamic effects of nisoldipine in patients with liver cirrhosis. British Journal of Pharmacology 89 (Suppl.): 482P, 1986

    Google Scholar 

  • Buckley MM-T, Grant SM, Goa KL, McTavish D, Sorkin EN. Diltiazem: a reappraisal of its pharmacological properties and therapeutic use. Drugs 39: 757–806, 1990

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Chandler MH, Schran HF, Cutler RE, Smith AJ, Gonasun LM, et al. The effect of renal function on the disposition of isradipine. Journal of Clinical Pharmacology 28: 1076–1080, 1988

    PubMed  CAS  Google Scholar 

  • Cheung WK, Sia LL, Woodward DL, Graveline JF, Desjardins RE, et al. Importance of oral dosing rate on the hemodynamic and pharmacokinetic profile of nilvadipine. Journal of Clinical Pharmacology 28: 1001–1007, 1988

    PubMed  CAS  Google Scholar 

  • Clozel JP, Caille G, Taeymans Y, Theroux P, Biron P, et al. Improved gas Chromatographic determination of diltiazem and deacetyldiltiazem in human plasma. Journal of Pharmaceutical Sciences 73: 207–209, 1984

    PubMed  CAS  Google Scholar 

  • Cole SCJ, Flanagan RJ, Johnston A, Holt DW. Rapid high-performance liquid Chromatographic method for the measurement of verapamil and norverapamil in blood plasma or serum. Journal of Chromatography 218: 621–629, 1981

    PubMed  CAS  Google Scholar 

  • Cook E, Clifton GG, Vargas R, Bienvenu G, Williams R, et al. Pharmacokinetics, pharmacodynamics and minimum effective clinical dose of intravenous nicardipine. Clinical Pharmacology and Therapeutics 47: 766–718, 1990

    Google Scholar 

  • Cox JO, O’Boyle CA, Mee F, Kelly J, Atkins N, et al. The antihypertensive efficacy of verapamil in the elderly evaluated by ambulatory blood pressure measurement. Journal of Human Hypertension 2: 41–47, 1988

    PubMed  CAS  Google Scholar 

  • Cremer KF, Pieper JA, Joyal M. Relationship between diltiazem concentration and hemodynamic responses. Clinical Pharmacology and Therapeutics 37: 188, 1985

    Google Scholar 

  • Dayer P, Leeman T, Striberni R. Dextromethorphan O-demethylation in liver microsomes as a prototype reaction to monitor cytodrome P450 dbi activity. Clinical Pharmacology and Therapeutics 45: 34–40, 1989

    PubMed  CAS  Google Scholar 

  • Devane JG, Kelly JG, Geoghegan B. Pharmacokinetic and invitro characteristics of sustained-release verapamil products. Drug Development and Industrial Pharmacy 16: 1233–1248, 1990

    CAS  Google Scholar 

  • Donnelly R, Elliott HL, Meredith PA, Reid JL. Acute and chronic nifedipine in essential hypertension: concentration effect relationships. Clinical Science 73: 54P, 1987

    Google Scholar 

  • Dow RJ, Graham DJM. A review of the human metabolism and pharmacokinetics of nicardipine hydrochloride. British Journal of Clinical Pharmacology 22 (Suppl. 3): 195S–202S, 1986

    CAS  Google Scholar 

  • Drayer DE. Pharmacodynamic and pharmacokinetic differences between drug enantiomers in humans: an overview. Clinical Pharmacology and Therapeutics 40: 125–133, 1986

    PubMed  CAS  Google Scholar 

  • Dunselman PHJM, Edgar B, Scaf AHJ, Kuntze CEE, Wesseling H. Pharmacokinetics of felodipine after intravenous and chronic administration in patients with congestive heart failure. British Journal of Clinical Pharmacology 28: 45–52, 1989

    PubMed  CAS  Google Scholar 

  • Dylewicz P, Kirch W, Santos SR, Hutt MJ, Monig H, et al. Bioavailability and elimination of nitrendipine in liver disease. European Journal of Clinical Pharmacology 32: 563–568, 1987

    PubMed  CAS  Google Scholar 

  • Echizen H, Eichelbaum M. Clinical pharmacokinetics of verapamil, nifedipine and diltiazem. Clinical Pharmacokinetics 11: 425–449, 1986

    PubMed  CAS  Google Scholar 

  • Edgar B, Aurell M, Johnsson G, Regårdh CG, Shandky C. Effects of impaired renal function on the pharmacokinetics of felodipine. Drugs 34 (Suppl. 3): 31–32, 1987b

    PubMed  Google Scholar 

  • Edgar B, Hoffman K-S, Lundborg P, Regårdh CG, Ronn Ø, et al. Absorption, distribution and elimination of felodipine in man. Drugs 29 (Suppl. 2): 9–15, 1985b

    PubMed  Google Scholar 

  • Edgar B, Lundborg P, Regårdh CG. Clinical pharmacokinetics of felodipine: a summary. Drugs 34 (Suppl. 3): 16–27, 1987c

    PubMed  CAS  Google Scholar 

  • Edgar B, Regårdh CG, Johnsson G, Johansson L, Lundborg P, et al. Felodipine kinetics in healthy men. Clinical Pharmacology and Therapeutics 38: 205–211, 1985a

    PubMed  CAS  Google Scholar 

  • Edgar B, Regårdh CG, Lundborg P, Romare S, Nyberg G, et al. Pharmacokinetic and pharmacodynamic studies of felodipine in healthy subjects after various single oral and intravenous doses. Biopharmaceutics and Drug Disposition 8: 253–248, 1987a

    Google Scholar 

  • Egros F, Moulin A, Le Dily J, Dufour A. Routine determination of a new 1–4 dihydropyridine, oxodipine in human plasma by high performance liquid chromatography with electrochemical detection. Journal of Liquid Chromatography 13: 1001–1011, 1990

    CAS  Google Scholar 

  • Eichelbaum M, Mikus G, Mast V, Fischer C, Kuhlmann V, et al. Pharmacokinetics and pharmacodynamics of nitrendipine in healthy subjects and patients with kidney and liver disease. Journal of Cardiovascular Pharmacology 12 (Suppl. 4): S6–S10, 1988

    PubMed  CAS  Google Scholar 

  • Eichelbaum M, Mikus G, Vogelgesang B. Pharmacokinetics of (+), (−) and (±)-verapamil after intravenous administration. British Journal of Clinical Pharmacology 17: 453–458, 1984

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Elliott HL. Calcium antagonists in the treatment of hypertension and angina pectoris in the elderly. Journal of Cardiovascular Pharmacology 13 (Suppl. 4): 12–16, 1989

    Google Scholar 

  • Elliott HL, Meredith PA, Reid JL, Faulkner JK. A comparison of the disposition of single oral doses of amlodipine in young and elderly subjects. Journal of Cardiovascular Pharmacology 12 (Suppl. 7): S64–S66, 1988

    PubMed  CAS  Google Scholar 

  • Eriksson VG, Hoffmann KJ, Simonsson R, Regårdh CG. Pharmacokinetics of the enantiomers of felodipine in the day after oral and intravenous administration of a pseudoracemic mixture. Xenobiotica 21: 75–84, 1991

    PubMed  CAS  Google Scholar 

  • Faulkner JK, McGibney D, Chasseaud LF, Perry JL, Taylor IW. The pharmacokinetics of amlodipine in healthy volunteers after single intravenous and oral doses and after 14 repeated oral doses given once daily. British Journal of Clinical Pharmacology 22: 21–25, 1986

    PubMed  CAS  Google Scholar 

  • Forette F, Bellet M, Henry JF, Hervy MP, Poyard-Salmeron C, et al. Effect of nicardipine in elderly hypertensive patients. British Journal of Clinical Pharmacology 20 (Suppl. 1): 125S–129S, 1985

    PubMed  Google Scholar 

  • Foster TS, Hamann SR, Richards VR, Bryant PJ, Graves DA, et al. Nifedipine kinetics and bioavailability after single intravenous and oral doses in normal subjects. Journal of Clinical Pharmacology 23: 161–170, 1983

    PubMed  CAS  Google Scholar 

  • Freedman SB, Richmond DR, Ashley JJ, Kelly DT. Verapamil kinetics in normal subjects and patients with coronary artery spasm. Clinical Pharmacology and Therapeutics 30: 644–652, 1981

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Gangji D, Juvent M, Niset G, Wathien M, Degreve M, et al. Study of the influence of nifedipine on the pharmacokinetics and pharmacodynamics of propranolol, metoprolol and atenolol. British Journal of Clinical Pharmacology 17: 29S–35S, 1984

    PubMed  Google Scholar 

  • Gengo FM, Fagan SC, Krol G, Bernhard H. Nimodipine disposition and haemodynamic effects in patients with cirrhosis and age-matched controls. British Journal of Clinical Pharmacology 23: 47–53, 1987

    PubMed  CAS  Google Scholar 

  • Gibaldi M, Perrier D. Drugs and the pharmaceutical sciences: pharmacokinetics, Vol. 15, 2nd ed., Marcel Dekker Inc., New York, 1982

    Google Scholar 

  • Goa KL, Sorkin EM. Nitrendipine: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the treatment of hypertension. Drugs 33: 123–155, 1987

    PubMed  CAS  Google Scholar 

  • Graefe KH, Liegler R, Wagender W, Ramsch KD, Schmitz H. Plasma concentration-response relationships for some cardiovascular effects of dihydropyridines in healthy subjects. Clinical Pharmacology and Therapeutics 43: 16–22, 1988

    PubMed  CAS  Google Scholar 

  • Graham DJM, Dow RJ, Hall DJ, Alexander DF, Mroszczak EJ, et al. The metabolism and pharmacokinetics of nicardipine hydrochloride in man. British Journal of Clinical Pharmacology 20: 23S–28S, 1985

    PubMed  CAS  Google Scholar 

  • Hansson L. The effect of dihydropyridine calcium antagonists in hypertensive patients with impaired renal function. Journal of Cardiovascular Pharmacology 14 (Suppl. 10): S36–S39, 1989

    PubMed  Google Scholar 

  • Harapat SR, Kates RE. High performance liquid chromatography analysis of verapamil II: simultaneous quantitation of verapamil and its active metabolite, norverapamil. Journal of Chromatography 181: 484–489, 1980

    PubMed  CAS  Google Scholar 

  • Higuchi S, Sasaki H, Sodo T. Determination of a new cerebral vasodilator, 2,6-dimethyl-4-(3-nitrophenyl)-l,4 dihydropyridine-3,5-dicarboxylic acid 3-(2-N-benzyl N-methylamino) ethyl ester hydrochloride (XC-93) in plasma by electron-capture gas chromatography. Journal of Chromatography 110: 301–307, 1975

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Hoglund P, Nilsson L-G. Pharmacokinetics of diltiazem and its metabolites after repeated multiple dose treatments in healthy volunteers. Therapeutic Drug Monitoring 11: 543–550, 1989

    PubMed  CAS  Google Scholar 

  • Holford NHG, Sheiner LB. Understanding the dose effect relationship: clinical application of pharmacokinetic/pharmacodynamic modelling. Clinical Pharmacokinetics 6: 429–453, 1981

    PubMed  CAS  Google Scholar 

  • 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

    Google Scholar 

  • Hoyo-Vadillo C, Castaneda-Hernandez G, Herrera JE, Vidal-Garate J, Moreno-Ramos A, et al. Pharmacokinetics of nifedipine slow release tablet in Mexican subjects: further evidence of forearm oxidation polymorphism. Journal of Clinical Pharmacology 29: 816–820, 1989

    PubMed  CAS  Google Scholar 

  • Jakobsen P, Mikkelsen EO, Laursen J, Jensen F. Determination of nimodipine by gas chromatography using electron-capture detection: external factors influencing nimodipine concentrations during intravenous administration. Journal of Chromatography 374: 383–387, 1986

    PubMed  CAS  Google Scholar 

  • Jesko LJ, Miller AK, Yeager RL, Chatterji DC. Rapid GC method for quantitation of nifedpine in serum using electron capture detection. Journal of Chromatographic Science 21: 415–419, 1983

    Google Scholar 

  • Jespersen CM, Fredericksen M, Hansen JF, Klitgaard NA. Circadian variation in the pharmacokinetics of verapamil. European Journal of Clinical Pharmacology 37: 613–615, 1989

    PubMed  CAS  Google Scholar 

  • Johnson BF, Wilson J, Marwaha R, Hoch K, Johnson J. The comparative effects of verapamil and a new dihydropyridine calcium channel blocker on digoxin pharmacokinetics. Clinical Pharmacology and Therapeutics 42: 66–71, 1987

    PubMed  CAS  Google Scholar 

  • Joyal M, Pieper J, Cremer K, Feldman RL, Pepine CJ. Pharmacodynamic aspects of intravenous diltiazem administration. American Heart Journal 111: 54–61, 1986

    PubMed  CAS  Google Scholar 

  • Kelly JG, Colgan BV, Galiano A, Egros F, Moulin A, et al. Oxodipine, a new antihypertensive dihydropyridine: pharmacokinetics after repeated oral doses in relation to the effect. 25th Anniversary International Symposium on Calcium Antagonists in Hypertension, Basel, February 11–12, 1988. Abstract no. 321, 1988

  • Kelly JG, Devane JG, Geoghegan B. Pharmacokinetic properties and antihypertensive efficacy of once-daily diltiazem. Journal of Cardiovascular Pharmacology 19: 957–963, 1991

    Google Scholar 

  • Kendall MJ, Jack DB, Laugher SJ, Lobo J, Smith SR. Lack of a pharmacokinetic interaction between nifedipine and the betaadrenoceptor blockers metoprolol and atenolol. British Journal of Clinical Pharmacology 18: 331–335, 1984

    PubMed  CAS  Google Scholar 

  • Kirch N, Hutt HJ, Heidemann LI, Ramsch K, Janisch HD, et al. Drug interactions with nitrendipine. Journal of Cardiovascular Pharmacology 6 (Suppl. 7): S982–S985, 1984b

    PubMed  CAS  Google Scholar 

  • Kirch N, Rahsch K-D, Duhrsen V, Onhaus EE. Clinical pharmacokinetics of nimodipine in normal and impaired renal function. International Journal of Clinical Pharmaceutical Research 4: 381–384, 1984a

    CAS  Google Scholar 

  • Kirch W, Stenzel J, Dylewicz P, Hutt HJ, Santos SR, et al. Influence of nisoldipine on haemodynamic effects and plasma levels of digoxin. British Journal of Clinical Pharmacology 22: 155–159, 1986

    PubMed  CAS  Google Scholar 

  • Klein HO, Lang R, Weiss E, Di Segni E, Libhaber C, et al. The influence of verapamil on serum digoxin concentration. Circulation 65: 998–1003, 1982

    PubMed  CAS  Google Scholar 

  • Kleinbloesem CH, Van Brummelen P, Faber H, Danhof M, Vermeulen NPE, et al. Variability in nifedipine pharmacokinetics and dynamics: a new oxidation polymorphism in man. Biochemical Pharmacology 33: 3721–3724, 1984a

    PubMed  CAS  Google Scholar 

  • Kleinbloesem CH, Van Brummelen P, Van Harten J, Danhof M, Breimer DD. Nifedipine: influence of renal function on pharmacokinetic/pharmacodynamic relationship. Clinical Pharmacology and Therapeutics 37: 563–574, 1985

    PubMed  CAS  Google Scholar 

  • Kleinbloesem CH, Van Brummelen P, Van de Linde JA, Voogd PJ, Breimer DD. Nifedipine: kinetics and dynamics in healthy subjects. Clinical Pharmacology and Therapeutics 35: 742–749, 1984b

    PubMed  CAS  Google Scholar 

  • Kohlhaw K, Wonigeit K, Frei V, Oldhafer K, Neumann K, et al. Effect of the calcium channel blocker diltiazem on cyclosporin A blood levels and dose requirements. Transplantation Proceedings 20: 572–574, 1988

    PubMed  CAS  Google Scholar 

  • Kurosawa S, Kurosawa N, Owada E, Soeda H, Ito K. Pharmacokinetics of diltiazem in patients with liver cirrhosis. International Journal of Clinical Pharmacology Research 10: 311–318, 1990

    PubMed  CAS  Google Scholar 

  • Laher MS, Kelly JG, Doyle GD, Carmody M, Donohoe JF, et al. Pharmacokinetics of amlodipine in renal impairment. Journal of Cardiovascular pharmacology 12 (Suppl. 7): S60–S63, 1988

    PubMed  Google Scholar 

  • Langley MS, Sorkin EM. Nimodipine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in cerebrovascular disease. Drugs 37: 669–699, 1989

    PubMed  CAS  Google Scholar 

  • Larsson R, Karlberg BE, Gelin A, Aberg J, Regårdh CE. Acute and steady-state pharmacokinetic and antihypertensive effects of felodipine in patients with normal and impaired renal function. Journal of Clinical Pharmacology 30: 1020–1030, 1990

    PubMed  CAS  Google Scholar 

  • Lasseter KC, Shanblen EC, Murdoch AA, Burkholder DE, Krol GJ, et al. Steady-state pharmacokinetics of nitrendipine in hepatic insufficiency. Journal of Cardiovascular Pharmacology 6 (Suppl. 7): S977–S981, 1984

    PubMed  CAS  Google Scholar 

  • Lederballe Pedersen O, Mikkelson E. Acute and chronic effects of nifedipine in arterial hypertension. European Journal of Clinical Pharmacology 14: 374–381, 1978

    Google Scholar 

  • Lee SM, Williams R, Warnock D, Emmett M, Wolbach RA. The effects of nicardipine in hypertensive subjects with impaired renal function. British Journal of Clinical Pharmacology 22: 297S–306S, 1986

    Google Scholar 

  • Lemmer B, Nold G, Behne S, Becker HJ, Liefhold J, et al. Chronopharmacology of oral nifedipine in healthy subjects and in hypertensive patients. European Journal of Pharmacology 183: 521, 1990

    Google Scholar 

  • Lettieri JT, Krol GJ, Yeh SC, Burkholder DE, Zinny N, et al. The effects of age and race on nitrendipine pharmacokinetics and pharmacodynamics. Journal of Cardiovascular Pharmacology 12 (Suppl. 4): S129–S132, 1988

    PubMed  CAS  Google Scholar 

  • Levine MAH, Ogilvie RI, Leenen FHH. Pharmacokinetic and pharmacodynamic interactions between nisoldipine and propranolol. Clinical Pharmacology and Therapeutics 43: 39–48, 1988

    PubMed  CAS  Google Scholar 

  • MacPhee GJA, Mclnnes GT, Agnew E, Brodie MJ. Clinically relevant adverse interaction between verapamil and carbamazepine in epileptic patients. British Journal of Clinical Pharmacology 21: 569–570, 1986

    Google Scholar 

  • Martre H, Sari R, Taburet AM, Jacobs C, Singlas E. Haemodialysis does not effect the pharmacokinetics of nifedipine. British Journal of Clinical Pharmacology 20: 155–158, 1985

    PubMed  CAS  Google Scholar 

  • Mazer N, Abisch E, Gfeller JC, Laplanache R, Bauerfeind P, et al. Intragastric behaviour and absorption kinetics of a normal and ‘floating’ modified-release capsule of isradipine under fasted and fed conditions. Journal of Pharmaceutical Sciences 77: 647–657, 1988

    PubMed  CAS  Google Scholar 

  • McLean AJ, Knight R, Harrison PM. Clearance-based oral drug interaction between verapamil and metoprolol and comparison with atenolol. American Journal of Cardiology 55: 1629–1627, 1985

    Google Scholar 

  • Meredith PA, Elliott HL, Ahmed JH, Reid JL. Age and the antihypertensive efficacy of verapamil: an integrated pharmacokinetic-pharmacodynamic approach. Journal of Hypertension 5 (Suppl. 5): S219–S221, 1987

    Google Scholar 

  • Meredith PA, Elliott HL, Kelman AW, Reid JL. A comparison of quinazoline alpha adrenoceptor antagonists by application of pharmacokinetic-pharmacodynamic modelling. Journal of Cardiovascular Pharmacology 7: 532–537, 1985

    PubMed  CAS  Google Scholar 

  • Mikus G, Fischer C, Heuer B, Langen C, Eichelbaum E. Application of stable isotope methodology to study the pharmacokinetics bioavailability and metabolism of nitrendipine after i.v. and p.o. administration. British Journal of Clinical Pharmacology 24: 561–569, 1987

    PubMed  CAS  Google Scholar 

  • Mikus G, Mast V, Fischer C, Machleidt C, Kuhlmann U, et al. Pharmacokinetics, bioavailability, metabolism and acute and chronic antihypertensive effects of nitrendipine in patients with chronic renal failure and moderate to severe hypertension. British Journal of Clinical Pharmacology 31: 313–322, 1991

    PubMed  CAS  Google Scholar 

  • Mooy J, Shols M, Van Baak M, Van Hoof M, Muytjens A, et al. Pharmacokinetics of verapamil in patients with renal failure. European Journal of Clinical Pharmacology 28: 405–410, 1985

    PubMed  CAS  Google Scholar 

  • Morselli PL, Rovei V, Mitchard M, Durard A, Goneni 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, pp. 152–168, Exerpta Medica, Amsterdam, 1979

    Google Scholar 

  • Niwa T, Tokuma Y, Noguchi H. Plasma protein binding of nilvadipine, a new dihydropyridine calcium antagonist, in man and dog. Research Communications in Chemical Pathology and Pharmacology 55: 75–78, 1987

    PubMed  CAS  Google Scholar 

  • O’Malley K, Cusack B, Kelly JG. Enzyme induction and first pas metabolism in man: effects of ageing. In Bezooijen (Ed.) Pharmacological, morphological and physiological aspects of liver aging, pp. 149–154, Eurage, The Netherlands, 1984

    Google Scholar 

  • O’Malley K, Kelly JG. Pharmacokinetics in the elderly. In Amery & Staessen (Eds) Handbook of hypertension: hypertension in the elderly, Vol. 12, pp. 186–194, Elsevier Science Publishers, Amsterdam, 1989

    Google Scholar 

  • Opie LH. Clinical use of calcium channel antagonist drugs, 2nd ed., Kluwer Academic Publishers, Boston, 1990

    Google Scholar 

  • Pasanisi F, Meredith PA, Reid JL. Pharmacokinetics of nifedipines: kinetics of nifedipine retard. International Journal of Clinical Pharmacology Research 5: 63–66, 1985

    PubMed  CAS  Google Scholar 

  • Pasanisi F, Reid JL. Plasma nifedipine levels and fall in blood pressure in a 53 year old woman. European Journal of Clinical Pharmacology 25: 143–144, 1983

    PubMed  CAS  Google Scholar 

  • Pedersen KE, Dorph-Pedersen A, Hvidt S, Klitgaard NA, Pedersen KK. The long-term effects of verapamil on plasma digoxin concentration and renal digoxin clearance in healthy subjects. European Journal of Clinical Pharmacology 22: 123–127, 1982

    PubMed  CAS  Google Scholar 

  • Piepho RW, Culbertson VL, Rhodes RS. Drug interactions with the calcium entry blockers. Circulation 75 (Suppl. V): V181–V194, 1987

    PubMed  CAS  Google Scholar 

  • Pietta P, Rava A, Bondi P. High performance liquid chromatography of nifedipine, its metabolites and photochemical degradation products. Journal of Chromatography 210: 561–521, 1981

    Google Scholar 

  • Porchet HC, Dayer P. Serum concentrations and effects of (±) nicardipine compared with nifedipine in a population of healthy subjects. Clinical Pharmacology and Therapeutics 48: 155–160, 1990

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Rahn KH, Mooy J, Bohm R. Reduction of bioavailability of verapamil by rifampicin. New England Journal of Medicine 312: 920–921, 1985

    PubMed  CAS  Google Scholar 

  • Ramsch KD, Ahr G, Tettenborn D, Auer LM. Overview on pharmacokinetics of nimodipine in healthy volunteers and in patients with subarachnoid haemorrhage. Neurochirurgia 28: 74–78, 1985

    PubMed  Google Scholar 

  • Ramsch KD, Lucker PW, Wetzelsburger N. Pharmacokinetics of intravenously and orally administered nimodipine. Clinical Pharmacology and Therapeutics 41: 216, 1987

    Google Scholar 

  • Ramsch KD, Sommer J. Pharmacokinetics and metabolism of nitrendipine. In Scriabne et al. (Eds) Nitrendipine, pp. 409–420, Urban and Schwarzenberg, Baltimore, 1984

    Google Scholar 

  • Razak TA, McNeill JJ, Sewell RB, Drummer OH, Smallwood Ra, et al. The effect of hepatic cirrhosis on the pharmacokinetics and blood pressure response to nicardipine. Clinical Pharmacology and Therapeutics 47: 463–469, 1990

    PubMed  CAS  Google Scholar 

  • Rehnqvist N, Billing E, Moberg L, Lundman T, Olsson G. Pharmacokinetics of felodipine and effect on digoxin plasma levels in patients with heart failure. Drugs 34 (Suppl. 3): 33–42, 1987

    PubMed  Google Scholar 

  • Rehnqvist N, Edgar B, Olsson R, Kendall M, Collste P, et al. Pharmacokinetics of felodipine in patients with liver disease. European Journal of Clinical Pharmacology 36: 473–479, 1989

    Google Scholar 

  • Reid JL, Meredith PA, Donnelly R, Elliott HL. Pharmacokinetics of calcium antagonists. Journal of Cardiovascular Pharmacology 12 (Suppl. 7): S22–S26, 1988

    PubMed  CAS  Google Scholar 

  • Reidenberg M. The binding of drugs to plasma proteins from patients with poor renal function. Clinical Pharmacokinetics 1: 121–125, 1976

    PubMed  CAS  Google Scholar 

  • Remme WJ, Van Hoogenhuyze DCA, Hofman A, Storm CJ, Krauss XH, et al. Acute antiischaemic properties of high dosages of intravenous diltiazem in humans in relation to its coronary and systemic haemodynamic effects. European Heart Journal 8: 965–974, 1987

    PubMed  CAS  Google Scholar 

  • Robertson DRC, Walker DG, Renwick AG, George CF. Age-related changes in the pharmacokinetics and pharmacodynamics of nifedipine. British Journal of Clinical Pharmacology 25: 297–305, 1988

    PubMed  CAS  Google Scholar 

  • Rosseel MT, Bogaert MG. Determination of nifedipine in human plasma by capillary gas chromatography with nitrogen detection. Journal of Chromatography 279: 675–680, 1983

    PubMed  CAS  Google Scholar 

  • Rovei V, Mitchard M, Morselli PL. Simple, sensitive and specific gas-chromatographic method for the quantification of diltiazem in human body fluids. Journal of Chromatography 138: 391–398, 1977

    CAS  Google Scholar 

  • Schoors DF, Vercruysse I, Musch G, Massart DL, Dupont AG. Influence of nicardipine on the pharmacokinetics and pharmacodynamics of propranolol in healthy volunteers. British Journal of Clinical Pharmacology 29: 497–501, 1990

    PubMed  CAS  Google Scholar 

  • Schran HF, Jaffe JM, Gonasum LM. Clinical pharmacokinetics of isradipine. American Journal of Medicine 84 (Suppl. 3B): 80–89, 1988

    Google Scholar 

  • Schwartz JB. Aging alters verapamil elimination and dynamics: single dose and steady state responses. Journal of Pharmacology and Experimental Therapeutics 255: 364–373, 1990

    PubMed  CAS  Google Scholar 

  • Schwartz JB, Abernethy DR. Responses to intravenous and oral diltiazem in elderly and younger patients with essential hypertension. American Journal of Cardiology 59: 1111–1117, 1987

    PubMed  CAS  Google Scholar 

  • Smith SR, Kendall MJ, Lobo J, Beerahee A, Jack DB, et al. Ranitidine and cimetidine: drug interactions with single dose and steady-state nifedipine administration. British Journal of Clinical Pharmacology 23: 311–315, 1987a

    PubMed  CAS  Google Scholar 

  • Smith SR, Wilkins MR, Jack DB, Kendall MJ, Laugher S. Pharmacokinetic interaction between felodipine and metoprolol. European Journal of Clinical Pharmacology 31: 576–578, 1987b

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Sorkin EM, Clissold SP, Brogden RN. 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, 1985

    PubMed  CAS  Google Scholar 

  • Suzuki H, Fujiwara S, Kondo S, Sugimoto I. Determination of nifedipine in human plasma by high performance liquid chromatography with electrochemical detection. Journal of Chromatography 341: 341–346, 1985

    PubMed  CAS  Google Scholar 

  • Taburet AM, Singlas E, Colin J-N, Banzet O, Thibonnier M, et al. Pharmacokinetic studies of nifedipine tablets: correlation with antihypertensive effects. Hypertension 5: II29–II33, 1983

    PubMed  CAS  Google Scholar 

  • Taeymans Y, Clozel JP, Caille G, Brevers G, Theroux P. Relationship between diltiazem plasma levels and its haemodynamic effects. Circulation 66: 11–81, 1982

    Google Scholar 

  • Tawashi M, Marc-Aurele J, Bichet D, Spenard J, Lariviere L, et al. Pharmacokinetics of diltiazem and five of its metabolites in patients with chronic renal failure. Biopharmaceutics and Drug Disposition 12: 95–104, 1991

    CAS  Google Scholar 

  • Terakawa M, Tokuma Y, Shishido A, Noguchi H. Pharmacokinetics of nilvadipine in healthy volunteers. Journal of Clinical Pharmacology 27: 111–117, 1987

    PubMed  CAS  Google Scholar 

  • Tokuma Y, Fujiwara T, Noguchi H. Determination of (+) and (−) nilvadipine in human plasma using chiral stationary phase liquid chromatography and gas chromatography-mass spectrometry and a preliminary pharmacokinetic study in humans. Journal of Pharmaceutical Sciences 76: 310–313, 1987

    PubMed  CAS  Google Scholar 

  • Tonolo G, Troffa C, Pazzola A, Melis MG, Manunta P, et al. Efficacy and tolerability of a new once-daily nifedipine formulation in mild to moderate essential hypertension. Current Therapeutic Research 47: 76–80, 1990

    Google Scholar 

  • Urien S, Albengres E, Comte A, Kiechel JR, Tillement JP. Plasma protein binding and erythrocyte partitioning of nicardipine in vitro. Journal of Cardiovascular Pharmacology 7: 891–898, 1985

    PubMed  CAS  Google Scholar 

  • Van Bortel L, Bohm R, Mooy J, Schiffers P, Rahn KH. Total and free steady-state plasma levels and pharmacokinetics of nifedipine in patients with terminal renal failure. European Journal of Clinical Pharmacology 37: 185–189, 1989a

    PubMed  Google Scholar 

  • Van Bortel L, Bohm R, Mooy J, Schiffers P, Rahn KH. Pharmacokinetics of nitrendipine in terminal renal failure. European Journal of Clinical Pharmacology 36: 467–471, 1989b

    PubMed  Google Scholar 

  • Van Harten J, Burggraaf J, Van Brummelen P, Breimer DD. Influence of renal function on the pharmacokinetics and cardiovascular effects of nisoldipine after single oral dosing. Clinical Pharmacokinetics 16: 55–64, 1989b

    PubMed  Google Scholar 

  • Van Harten J, Lodewijks MThM, Guyt-Scholten JW, Van Brummelen P, Breimer DD. Gas Chromatographic determination of nisoldipine and one of its metabolites in plasma. Journal of Chromatography 423: 327–333, 1987

    PubMed  Google Scholar 

  • Varr Harten J, Van Brummelen P, Danhof M, Quekel RPCH, Breimer DD. Pharmacokinetics of long-term nisoldipine treatment in hypertensive patients. Journal of Cardiovascular Pharmacology 13: 624–629, 1989a

    Google Scholar 

  • Van Harten J, Van Brummelen P, Lodewijks MThM, Danhof M, Breimer DD. Pharmacokinetics and haemodynamic effect of nisoldipine and its interaction with cimetidine. Clinical Pharmacology and Therapeutics 43: 332–341, 1988b

    PubMed  Google Scholar 

  • Van Harten J, Van Brummelen P, Ooms P, Danhof M, Baluw GJ, et al. Variability in the pharmacokinetics of nisoldipine as caused by differences in liver blood flow response. Journal of Clinical Pharmacology 29: 714–721, 1989c

    PubMed  Google Scholar 

  • Van Harten J, Van Brummelen P, Wilson JH, Lodewijks MT, Breimer DD. Nisoldipine: kinetics and effects in blood pressure and heart rate in patients with liver cirrhosis after intravenous and oral administration. European Journal of Clinical Pharmacology 34: 387–394, 1988a

    PubMed  Google Scholar 

  • Vercrysse F, Schoors DF, Musch G, Massart DL, Dupont AG. Nicardipine does not influence the pharmacokinetics and pharmacodynamics of atenolol. British Journal of Clinical Pharmacology 30: 499–500, 1990

    Google Scholar 

  • Vogelgesang B, Echizen H, Schmidt E, Eichelbaum M. Stereoselective first pass metabolism of highly cleared drugs: studies of the bioavailability of L- and D-verapamil examined with a stable isotope technique. British Journal of Clinical Pharmacology 18: 733–740, 1984

    PubMed  CAS  Google Scholar 

  • Warrington SJ, Holt D, Johnston A, Fitzsimons TJ. Pharmacokinetics an pharmacodynamics of verapamil in combination with atenolol, metoprolol and propranolol. British Journal of Clinical Pharmacology 17: 37S–44S, 1984

    PubMed  Google Scholar 

  • Wei JY. Use of calcium entry blockers in elderly patients: special considerations. Circulation 80 (Suppl. 6): 171–177, 1989

    Google Scholar 

  • Weir MR, Josselson J, Giard MJ. Sustained-release diltiazem compared with atenolol monotherapy for mild to moderate hypertension. American Journal of Cardiology 60: 361–411, 1987

    Google Scholar 

  • Wilkinson GR, Shand DG. A physiological approach to hepatic drug clearance. Clinical Pharmacology and Therapeutics 18: 377–390, 1975

    PubMed  CAS  Google Scholar 

  • Wing LMH, Miners JO, Lillywhite KJ. Verapamil disposition effects of sulphinpyrazone and cimetidine. British Journal of Clinical Pharmacology 19: 385–391, 1985

    PubMed  CAS  Google Scholar 

  • Winship LC, McKenney JM, Wright JJ, Wood JH, Goodman RP. The effect of ranitidine and cimetidine on single-dose diltiazem pharmacokinetics. Pharmacotherapy 5: 16–19. 1985

    PubMed  CAS  Google Scholar 

  • Wu AT, Masseg IJ, Kushinsky S. A high-performance liquid Chromatographic method for the simultaneous determination of nicardipine and its pyridine metabolite II in plasma. Journal of Pharmaceutical Science 73: 1444–1447, 1984

    CAS  Google Scholar 

  • Zilly W, Ramsch KD, Gothe M. Disposition of nitrendipine in patients with chronic liver disease. Journal of Cardiovascular Pharmacology 12 (Suppl. 4): S175–S177, 1988

    PubMed  Google Scholar 

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Kelly, J.G., O’Malley, K. Clinical Pharmacokinetics of Calcium Antagonists. Clin. Pharmacokinet. 22, 416–433 (1992). https://doi.org/10.2165/00003088-199222060-00002

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