Summary
Five identical (monozygotic) and 6 fraternal (dizygotic) sets of healthy twins between 47 and 53 years of age were given a single oral dose of nortriptyline (NT) hydrochloride 1 mg/kg. The plasma half-life, the apparent volume of distribution, and the plasma clearance of NT were estimated for each subject as well as the urinary excretion rate of conjugated and unconjugated 10-hydroxynortriptyline (10-OH-NT). “Steady-state” plasma levels predicted from the reciprocal single dose plasma clearance rate of NT agreed well with those observed in a previous study of the same twins 2 years previously. In the present study, there was a 5-fold range of the plasma half-lives and 2-fold variation in the apparent volume of distribution of NT (assuming complete availability on oral administration). No correlation was found between the plasma half-life and the apparent volume of distribution. Analysis of variance showed that most of the variability between persons in plasma half-life, apparent volume of distribution and conjugation of 10-OH-NT was genetically determined. The plasma half-life and apparent volume of distribution may contribute independently to the total interindividual variability of the “steady-state” plasma level of NT.
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References
Alexanderson, B.: Pharmacokinetics of nortriptyline in man after single and multiple oral doses: The predictability of steady-state plasma concentrations from single-dose plasma-level data. Europ. J. clin. Pharmacol.4, 82–91 (1972a).
Alexanderson, B.: Pharmacokinetics of desmethylimipramine and nortriptyline in man after single and multiple oral doses — a cross-over study. Europ. J. clin. Pharmacol.5, 1–10 (1972b).
Alexanderson, B., Borgå, O.: Interindividual differences in plasma protein binding of nortriptyline in man — a twin study. Europ. J. clin. Pharmacol.4, 196–200 (1972).
Alexanderson, B., Borgå, O.: Urinary excretion of nortriptyline and five of its metabolites in man after single and multiple oral doses. Europ. J. clin. Pharmacol.5, 174–180 (1973).
Alexanderson, B., Sjöqvist, F.: Individual differences in the pharmacokinetics of monomethylated tricyclic antidepressants: role of genetic and environmental factors and clinical importance. N.Y. Acad. Sci.179, 739–751 (1971).
Alexanderson, B., Borgå, O., Alván, G.: The availability of orally administered nortriptyline. Europ. J. clin. Pharmacol.5, 181–185 (1973).
Alexanderson, B., Evans, D.A.P., Sjöqvist, F.: Steady-state plasma levels of nortriptyline in twins: Influence of genetic factors and drug therapy. Brit. med. J.4, 764–768 (1969).
Borgå, O., Garle, M.: A gas chromatographic method for the determination of nortriptyline and some of its metabolites in human plasma and urine. J. Chromatogr.68, 77–88 (1972).
Borgå, O., Palmér, L., Linnarsson, A., Holmstedt, B.: Quantitative determination of nortriptyline and desmethylnortripty-line in human plasma by combined gas chromatography-mass spectrometry. Anal. Letters4, 837–849 (1971).
Braithwaite, R.A., Widdop, B.: A specific gas-chromatographic method for the measurement of “steady-state” plasma levels of amitriptyline and nortriptyline in patients. Clin. chim. Acta35, 461–472 (1971).
Braithwaite, R.A., Goulding, R., Theano, G., Bailey, J., Coppen, A.: Plasma concentrations of amitriptyline and clinical response. Lancet1972 I, 1297–1300.
Cucinell, S.A., Perl, W.: Application of clearance and volume of distribution to the plateau principle of drugs. J. Pharm. Sci.59, 1423–1427 (1970).
Gibaldi, M., Nagashima, R., Levy, G.: Relationship between drug concentration in plasma or serum and amount of drug in the body. J. Pharm. Sci.58, 193–197 (1969).
Gibaldi, M., Boyes, R.N., Feldman, S.: Influence of first-pass effect on availability of drugs on oral administration. J. Pharm. Sci.60, 1338–1340 (1971).
Hammer, W., Ideström, C.-M., Sjöqvist, F.: Chemical control of antidepressant drug therapy. In: Garratini, S., Dukes, M. N.G. (eds.), Proc. First. Internat. Symp. Antidepressant Drugs, Milan, Italy 1966, Excerpta med. Int. Congr. Ser. No. 122, 301–310 (1966).
Kragh-Sørensen, P., Åsberg, M., Eggert-Hansen, C.: Plasma nortriptyline levels in endogenous depression. Lancet1973 I, 113–115.
Moody, J.P., Tait, A.C., Todrick, A.: Plasma levels of imipramine and desmethylimipramine during therapy. Brit. J. Psychiat.113, 183–193 (1967).
Schildkraut, J.J., Kety, S.S.: Biogenic amines and emotion. Science156, 21–30 (1967).
Sjöqvist, F., Alexanderson, B., Åsberg, M., Bertilsson, L., Borgå, O., Hamberger, B., Tuck, D.: Pharmacokinetics and biological effects of nortriptyline in man. Acta Pharmacol. Toxicol.29, (Suppl. 3) 255–280 (1971).
Snedechor, G.W., Cochran, W.G.: Statistical methods, 6th ed., p. 285. Ames: Iowa State University Press 1967.
Strandell, T., Erwald, R., Kulling, K.G., Lundbergh, P. Marions, O., Wiechel, K.L.: Simulataneous determination of portal vein and hepatic artery blood flow by indicator dilution technique in awake man. Preliminary report. Acta med. scand.191, 139–140 (1972).
Wagner, J.G.: Pharmacokinetics. Grosse Pointe, Michigan: J.M. Richards Laboratory (ed.) 1969.
Wagner, J.G., Northam, J.I., Alway, C.D., Carpenter, O.S.: Blood levels of drug at equilibrium state after multiple dosing. Nature (London)207, 1301–1302 (1965).
Åsberg, M., Cronholm, B., Sjöqvist, F., Tuck, D.: The correlation of subjective side-effects with plasma concentrations of nortriptyline. Brit. med. J.4, 18–21 (1970).
Åsberg, M., Cronholm, B., Sjöqvist, F., Tuck, D.: Relationship between plasma level and therapeutic effect of nortriptyline. Brit. med. J.3, 331–334 (1971a).
Åsberg, M., Evans, D.A.P., Sjöqvist, F.: Genetic control of nortriptyline kinetics in man: A study of the relatives of propositi with high plasma concentration. J. med. Genetics8, 129–135 (1971b).
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Alexanderson, B. Prediction of steady-state plasma levels of nortriptyline from single oral dose kinetics: A study in twins. Eur J Clin Pharmacol 6, 44–53 (1973). https://doi.org/10.1007/BF00561800
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DOI: https://doi.org/10.1007/BF00561800