Summary
The pharmacokinetic parameters and oral bioavailability of the antiarrhythmic drug verapamil were determined in six patients with atrial fibrillation. Plasma samples were taken following i.v. injection of verapamil 10 mg (Isoptin® 2 ml), and oral verapamil 80 mg (Isoptin® 2 tablets of 40 mg). Verapamil and its N-demethylated metabolite, norverapamil, were analyzed to 1 ng/ml plasma by gas chromatography-mass spectrometry using deuterated standards. Following intravenous injection, the disposition of verapamil followed a biexponential pattern with a fast distribution phase and a slower elimination phase (t1/2β=5.79 h), corresponding to a plasma clearance of 0.26 1/kg/h. After oral administration, only an elimination phase was evident, with the same elimination rate (t1/2β=5.53 h). The oral bioavailability was 10.5%±7.5%. The norverapamil formed after i.v. and oral administration of verapamil had plasma half-lives of 5.86 h and 6.77 h, respectively. The elimination of verapamil in patients with atrial fibrillation was decreased compared to that in healthy young volunteers and the oral bioavailability was lower. Very good correlation between the percentage reduction in heart rate and the log plasma concentration of verapamil was found in every patient during the elimination phase, irrespective of the route of administration. There was also a high correlation when the plasma concentration — effect data from all the patients were pooled (r=0.59,n=71;p<0.0005).
Similar content being viewed by others
References
McAllister RG, Howell SM (1976) Fluorometric assay of verapamil in biological fluids and tissues. J Pharm Sci 65:431–432
McAllister RG, Tan TG, Bourne DWA (1979) GLC assay of verapamil in plasma: Identification of fluorescent metabolites after oral drug administration. J Pharm Sci 68:574–577
Collste P, Borg K-O, Åström H, von Bahr C (1979) Contribution of 4-hydroxy-alprenolol to adrenergic beta receptor blockade of alprenolol. Clin Pharmacol Ther 25:416–422
Dominic J, McAllister RG, Kuo C-S, Reddy CP, Surawicz B (1979) Verapamil plasma levels and ventricular rate response in patients with atrial fibrillation and flutter. Clin Pharmacol Ther 26:710–714
Eichelbaum M, Ende M, Remberg G, Schomerus M, Dengler HJ (1979) The metabolism of DL-[14C] verapamil in man. Drug Metab Dispos 7:145–148
Eichelbaum M, Somogyi A, von Unruh GE, Dengler HJ (1981) Simultaneous determination of the intravenous and oral pharmacokinetic parameters of D, L-verapamil using stable isotopelabelled verapamil. Eur J Clin Pharmacol 19:133–137
Fleckenstein A, Tritthart H, Fleckenstein B, Herbst A, Grün G (1969) Eine neue Gruppe kompetitiver Ca++-Antagonisten (Iproveratril, D600, Prenylamin) mit starken Hemmeffekten auf die elektromechanische Koppelung im Warmblüter-Myokard. Pfluegers Arch 307:R 25
Fleckenstein A (1972) Physiologie und Pharmakologie der transmembranären Natrium-, Kalium- und Calcium-Bewegungen. Arzneim Forsch 22:2019–2028
Harapat SR, Kates RE (1979) Rapid high-pressure liquid chromatographic analysis of verapamil in blood and plasma. J Chromatogr 170:385–390
Harapat SR, Kates RE (1980) High-performance liquid chromatographic analysis of verapamil. II. Simultaneous quantitation of verapamil and its active metabolite, norverapamil. J Chromatogr 181:484–489
Hartvig P, Ahnfeldt NO, Hammarlund M, Vessman J (1979) Analysis of nicotine as a trichloroethyl carbamate by gas chromatography with electron-capture detection. J Chromatogr 173:127–138
Hege HG (1979) Gas chromatographic determination of verapamil in plasma and urine. Arzneim Forsch 29:1681–1684
Jaouni TM, Leon MB, Rosing DR and Fales HM (1980) Analysis of verapamil in plasma by liquid chromatography. J Chromatogr 182:473–477
Johnston A, Burgess CD and Hamer J (1981) Systemic availability of oral verapamil and effect on PR interval in man. Br J Clin Pharmacol 12:397–400
Karlsson K-E (1981) Derivatization of tertiary amines with chloroformate esters for gas chromatographic analysis. Thesis, Uppsala 1981
Kohlhardt M, Bauer B, Krause H, Fleckenstein A (1972) New selective inhibitors of the transmembrane Ca conductivity in mammalian myocardial fibres. Studies with the voltage clamp technique. Experientia 28:288–289
Koike Y, Shimamura K, Shudo I, Saito H (1979) Pharmacokinetics of verapamil in man. Res Commun Chem Pathol Pharmacol 24:37–47
Loo JCK, Riegelman S (1970) Assessment of pharmacokinetic constants from postinfusion blood curves obtained after iv infusion. J Pharm Sci 59:53–55
Nayler WG, Krikler D (1974) Verapamil and the myocardium. Postgrad Med J 50:441–446
Neugebauer G (1978) Comparative cardiovascular actions of verapamil and its major metabolites in the anaesthetised dog. Cardiovasc Res 12:247–254
Remberg G, Ende M, Eichelbaum M, Schomerus M (1980) Mass spectrometric identification of DL-verapamil metabolites. Arzneim Forsch 30:398–401
Schomerus M, Spiegelhalder B, Stieren B, Eichelbaum M (1976) Physiological disposition of verapamil in man. Cardiovasc Res 10:605–612
Singh BN, Ellrodt G, Peter CT (1978) Verapamil: A review of its pharmacological properties and therapeutic use. Drugs 15:169–197
Spiegelhalder B, Eichelbaum M (1977) Determination of verapamil in human plasma by mass fragmentography using stable isotope-labelled verapamil as internal standard. Arzneim Forsch 27:94–97
Taskinen J, Klinge E (1980) Pharmacokinetics of verapamil and its N-dealkylated metabolites after a conventional and slow release tablet (1980) World Conference on Clinical Pharmacology and Therapeutics, London 3–9 August 1980, Abstract 0424
Woodcock BG, Hopf R and Kaltenbach M (1980) Verapamil and norverapamil plasma concentrations during long-term therapy in patients with hypertrophic obstructive cardiomyopathy. J Cardiovasc Pharm 2:17–23
Woodcock BG, Rietbrock I, Vöhringer HF, Rietbrock N (1981a) Verapamil disposition in liver disease and intensive-care patients: Kinetics, clearance, and apparent blood flow relationships. Clin Pharmacol Ther 29:27–34
Woodcock BG, Schulz W, Kober G, Rietbrock N (1981b) Direct determination of hepatic extraction of verapamil in cardiac patients. Clin Pharmacol Ther 30:52–56
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Anderson, P., Bondesson, U. & Sylvén, C. Clinical pharmacokinetics of verapamil in patients with atrial fibrillation. Eur J Clin Pharmacol 23, 49–57 (1982). https://doi.org/10.1007/BF01061377
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01061377