European Journal of Clinical Pharmacology

, Volume 5, Issue 3, pp 158–165 | Cite as

Ro 3-3528, a β-adrenoceptor blocking agent: Oral and intravenous pharmacokinetic studies in normal volunteers

  • E. M. Phillips
  • D. Hicks
Originals

Summary

Plasma levels of Ro 3-3528 have been measured fluorimetrically in man following oral and intravenous administration. Peak plasma levels, and the time at which peak was reached, varied widely between fasting subjects following oral administration, but identical dosage repeated in an individual produced comparable results. The mean half-life of Ro 3-3528 orally was 2.31 h (S.D.±0.35): after intravenous administration there was a biexponential fall in plasma levels; the early phase with a half-life of five minutes consistent with rapid redistribution of Ro 3-3528 from plasma to other tissue compartments, and a late phase with a mean half-life of 2.42 h (S.D.±0.33) representing concurrent metabolism and excretion. The effect of Ro 3-3528 on exercise tachycardia in normal volunteers was assayed against that of propranolol and of placebo by oral and intravenous routes. Dose dependent inhibition of exercise tachycardia was shown for both drugs by each route of administration. The dose ratio of propranolol to Ro 3-3528 was 1:3.5—6 orally and 1:5—6 intravenously. The effect of exercise on the volume of distribution of drugs is discussed. The use of a multivariate analysis in evaluation of pharmacokinetic studies is considered.

Key words

Exercise tachycardia spectrophotofluorimetry β-adrenoceptor blocking drugs multivariate analysis 

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References

  1. Arbab, A.G., Hicks, D.C., Turner, P.: Relative potency of intravenous prinodolol and propranolol in man. B.J. Pharmacol.42, 665–666 (1971).Google Scholar
  2. Black, J.W., Duncan, W.A.M., Shanks, R.G.: Comparison of some properties of pronethalol and propranolol. Brit. J. Pharmacol.25, 577–591 (1965).Google Scholar
  3. Brick, I., Hutchison, K.J., McDevitt, D.G., Roddie, I.C., Shanks, R.G.: Comparison of the effects of I.C.I. 50.172 and propranolol on the cardiovascular responses to adrenaline, isoprenaline and exercise. Brit. J. Pharmacol.34, 127–140 (1968).Google Scholar
  4. Chamberlain, D.A., Turner, P., Sneddon, J.M.: Effects of atropine on heart-rate in healthy man. Lancet1967 II, 12–15.Google Scholar
  5. Cherrington, Norma, Smart, J.V.: Some multivariate statistical techniques applied to pharmacological research. Brit. J. Pharmacol.41, 425 (1971).Google Scholar
  6. Coltart, D.J., Shand, D.G.: Plasma propranolol levels in the quantitative assessment of β-adrenergic blockade in man. Brit. med. J.1970 III, 731–734.Google Scholar
  7. Epstein, S.E., Robinson, B.F., Kahler, R.L., Braunwald, E.: Effects of beta-adrenergic blockade on the cardiac response to maximal and submaximal exercise in man. J. clin. Invest.44, 1745–1753 (1965).Google Scholar
  8. Haefely, W., Hürlimann, A., Thoenen, H.: 6,7-Dimethyl-α-(isopropylamino) methyl-2-benzofuranulmethanol hydrochloride. Some pharmacological actions of the β-adrenolytic agent Ro 3-3528. Angiologica4, 203–215 (1967).Google Scholar
  9. Hammer, W., Martens, S., Sjöqvist, F.: A comparative study of the metabolism of desmethylimipramine, nortriptyline, and oxyphenylbutazone in man. Clin. Pharm. Ther.10, 44–49 (1969).Google Scholar
  10. Hill, R.C., Turner, P.: The effects of a new beta-adrenoceptive receptor blocking drug on heart rate in man. Brit. J. Pharmacol.32, 663–670 (1968).Google Scholar
  11. J. Hornby.: M.Sc. Thesis. London, 1969.Google Scholar
  12. Long, R.F., Francis, R.J.: (Biochemical Division, Roche Products, England.) Personal communication.Google Scholar
  13. Paterson, J.W., Conolly, M.E., Dollery, C.T.: The pharmacodynamics and metabolism of propranolol in man. Pharmacol. Clin.2, 127–133 (1970).Google Scholar
  14. Robinson, B.F., Epstein, S.E., Beiser, G.D., Braunwald, E.: Control of heart rate by the autonomic nervous system. Studies in man on the interrelation between baroreceptor mechanisms and exercise. Circulat. Res.19, 400–411 (1966).Google Scholar
  15. Van Rossum, J.M., Tomey, A.H.M.: Rate of accumulation and plateau plasma concentration of drugs after chronic medication. J. Pharm. Pharmacol.20, 390–392 (1968).Google Scholar
  16. Shand, D.G., Nuckolls, E.M., Oates, J.A.: Plasma propranolol levels in adults with observations in four children. Clin. Pharmacol. Therap.11, 112–120 (1970).Google Scholar
  17. Shanks, R.G.: The properties of beta-adrenergic blocking agents. I.J. Med. Sci.2, 351–367 (1969).Google Scholar
  18. Smart, J.V.: Personal communication.Google Scholar
  19. Turner, P., Hill, R.C.: A comparison of three beta adrenergic receptor blocking drugs in thyrotoxic tachycardia. J. clin. Pharmacol.8, 268–271 (1968).Google Scholar
  20. Wade, O.L., Bishop, J.M.: Introduction by Donald, K.W.: Cardiac output and regional blood flow. Oxford: Blackwell Scientific Publ. 1962.Google Scholar

Copyright information

© Springer-Verlag 1973

Authors and Affiliations

  • E. M. Phillips
    • 1
  • D. Hicks
    • 1
  1. 1.Department of Clinical PharmacologySt. Bartholomew's HospitalLondonGreat Britain

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