Skip to main content
SpringerLink
Log in

Microdialysis Evaluation of the Ocular Pharmacokinetics of Propranolol in the Conscious Rabbit

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose. This study was conducted to assess the effects of anesthesia and aqueous humor protein concentrations on ocular disposition of propranolol.

Methods. Rabbits were anesthetized and a microdialysis probe was inserted into the anterior chamber of one eye; the contralateral eye served as a control. At timed intervals after probe placement, a 100-μl sample of aqueous humor was aspirated from each eye to determine protein concentration. In vitro protein binding parameters were used to simulate the impact of protein concentration on propranolol disposition. To assess the influence of anesthesia, probes were implanted in the anterior chamber of each eye. After >5-day stabilization, conscious and anesthetized rabbits (n = 3/group) received a 200-μg topical dose of [3H] DL-propranolol in each eye; propranolol was assayed in probe effluent.

Results. Changes in aqueous humor protein concentrations were observed following probe insertion. Simulations demonstrated that the unbound propranolol AUC (∼2.4-fold) in aqueous humor should be reduced due to protein influx. Intraocular propranolol exposure in anesthetized rabbits was ∼8-fold higher than in conscious rabbits, and ∼1.9-fold higher than in rabbits without a post-surgical recovery period.

Conclusions. Anesthesia and time-dependent aqueous humor protein concentrations may alter ocular pharmacokinetics, and must be taken into account in the design of microdialysis experiments.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. J. Waga, A. Ohta, and B. Ehinger. Intraocular microdialysis with permanently implanted probes in rabbit. ACTA Ophthalmologica. 69:618-624 (1991).

    PubMed  Google Scholar 

  2. J. Ben-Nun, D. A. Joyce, R. L. Cooper, and S. J. Cringle. Pharmacokinetics of intravitreal injection. Invest. Ophthalmol. Vis. Sci. 30:1055-1061 (1989).

    PubMed  Google Scholar 

  3. N. Stempels, M-J. Tassignon, and S. Sarre. A removable ocular microdialysis system for measuring vitreous biogenic amines. Graefe's Arch. Clin. Exp. Ophthalmol. 231:651-655 (1993).

    Google Scholar 

  4. P. Louzada-Junior, J. J. Dias, W. F. Santos, J. J. Lachat, H. F. Bradford, and J. Coutinho-Netto. Glutamate release in experimental ischaemia of the retina: an approach using microdialysis. J. Neurochem. 59:358-363 (1992).

    PubMed  Google Scholar 

  5. G. Tsai, G. Forloni, M. B. Robinson, B. L. Stauch, and J. T. Coyle. Calcium-dependent evoked release of N-[3H]Acetylaspartylglutamate from the optic pathway. J. Neurochem. 51:1956-1959 (1998).

    Google Scholar 

  6. H. Sato, S. Fukuda, M. Inatomi, R. Koide, N. Uchida, Y. Kanda, Y. Kiuchi, and K. Oguchi. Pharmacokinetics of norfloxacin and lomefloxacin in domestic rabbit aqueous humor analyzed by microdialysis. J. Jpn. Ophthalmol. 7:513-519 (1995).

    Google Scholar 

  7. K. D. Rittenhouse, R. L. Peiffer Jr., and G. M. Pollack. Evaluation of microdialysis sampling of aqueous humor for in vivo models of ocular absorption and disposition. J. Pharm. Biomed. Anal. 16:951-959 (1998).

    PubMed  Google Scholar 

  8. R. Ohtori, H. Sato, S. Fukuda, T. Ueda, R. Koide, Y. Kanda, Y. Kiuchi, and K. Oguchi. Pharmacokinetics of topical beta-adrenergic antagonists in rabbit aqueous humor evaluated with the microdialysis method. Exp. Eye. Res. 66:487-494 (1998).

    PubMed  Google Scholar 

  9. E. Noack. Treatment of glaucoma with beta-receptor blockers. Significance of adrenergic receptors of the beta-2 subtype for their effect on intraocular pressure. Ophthalmologica. 196:76-81 (1988).

    PubMed  Google Scholar 

  10. F. E. Ross, H. C. Innemee, and P. A. Van Zwieten. Ocular penetration of β-adrenergic blocking agents. An experimental study with atenolol, metoprolol, timolol and propranolol. Documenta Ophthalmoligica. 48:291-301 (1979).

    Google Scholar 

  11. D. F. Cole. Secretion of the aqueous humor. Exp. Eye Res. 25(suppl.):161-176 (1977).

    PubMed  Google Scholar 

  12. P. S. Kulkarni and B. D. Srinvasan. Nonsteroidal anti-inflammatory drugs in ocular inflammatory conditions in: A. J. Lewis, D. E. Furst eds., Nonsteroidal Anti-Inflammatory Drugs. Marcel Dekker, New York, 1987.

    Google Scholar 

  13. M. Rowland and T. N. Tozer. Clinical Pharmacokinetics: Concepts and Applications. 3rd ed. Media, PA: Williams and Wilkins, 1995.

    Google Scholar 

  14. L. L. Stale in: Robinson LE, Justice JB Jr., eds. Microdialysis in the Neurosciences. Amsterdam: Elsevier, 1991.

    Google Scholar 

  15. O. H. Lowry, J. J. Rosebrough, A. L. Farr, and R. J. Randall. Protein measurement with Folin phenol reagent. J. Biol. Chem. 193:265-275 (1951).

    PubMed  Google Scholar 

  16. J. D. Wright, F. D. Boudinot, and M. R. Ujhelyi. Measurement and analysis of unbound drug concentrations. Clin Pharmacokinet. 30:445-462 (1996).

    PubMed  Google Scholar 

  17. M. Gibaldi and D. Perrier. Pharmacokinetics, 2nd ed. New York: Marcel Dekker, 1982.

    Google Scholar 

  18. A. M. Herrera, D. O. Scott, and C. E. Lunte. Microdialysis sampling for determination of plasma protein binding of drugs. Pharm. Res. 7:1077-1081 (1990).

    PubMed  Google Scholar 

  19. S. Glasson, R. Zini, P. D'Athis, J. P. Tillement, and J. R. Boissier. The distribution of bound propranolol between different human serum proteins. Mol. Pharmacol. 17:187-191 (1980).

    PubMed  Google Scholar 

  20. Masuda K, Izawa Y, and Mishima S. Breakdown of the blood:aqueous barrier and prostaglandins. Bibliotheca Anatomica. 16:99-104 (1977).

    PubMed  Google Scholar 

  21. E. Latoure, J. Y. Driot, C. Coquelet, and C. Bonne. The role of platelets in blood-aqueous barrier breakdown induced by anterior paracentesis in the rabbit. Curr. Eye Res. 8:1105-1110 (1989).

    PubMed  Google Scholar 

  22. M. M. Tahery and D. A. Lee. Review: pharmacologic control of would healing in glaucoma filtration surgery. J. Ocul. Pharmacol. 5:155 (1989).

    PubMed  Google Scholar 

  23. C. Schmitt, V. J. Lotti, and J. C. LeDovarec. Penetration of five beta-adrenergic antagonists into the rabbit eye after ocular instillation. Albrecht von Graefes Arch. Klin. Ophthalmol. 217:167-174 (1981).

    Google Scholar 

  24. A. Hussain, S. Hirai, and J. Sieg. Ocular absorption of propranolol in rabbits. J. Pharm. Sci. 69:738-739 (1980).

    PubMed  Google Scholar 

  25. J. W. Sieg and J. R. Robinson. Vehicle effect on ocular drug bioavailability I: evaluation of fluorometholone. J. Pharm. Sci. 64:931-936 (1980).

    Google Scholar 

  26. S. S. Chrai, T. F. Patton, A. Mehta, and J. R. Robinson. Lacrimal and instilled fluid dynamics in rabbit eyes. J. Pharm. Sci. 62:1112-1121 (1973).

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, 27599-7360

    Kay D. Rittenhouse & Gary M. Pollack

  2. Departments of Ophthalmology and Pathology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, 27599-7040

    Robert L. Peiffer Jr.

Authors
  1. Kay D. Rittenhouse
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert L. Peiffer Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gary M. Pollack
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gary M. Pollack.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rittenhouse, K.D., Peiffer, R.L. & Pollack, G.M. Microdialysis Evaluation of the Ocular Pharmacokinetics of Propranolol in the Conscious Rabbit. Pharm Res 16, 736–742 (1999). https://doi.org/10.1023/A:1018884826943

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1018884826943

Search

Navigation