October 1991
Volume 32, Issue 11
Free
Articles  |   October 1991
Pharmacokinetic basis for nonadditivity of intraocular pressure lowering in timolol combinations.
Author Affiliations
  • V H Lee
    Department of Pharmaceutical Sciences, University of Southern California, School of Pharmacy, Los Angeles 90033.
  • A M Luo
    Department of Pharmaceutical Sciences, University of Southern California, School of Pharmacy, Los Angeles 90033.
  • S Y Li
    Department of Pharmaceutical Sciences, University of Southern California, School of Pharmacy, Los Angeles 90033.
  • S K Podder
    Department of Pharmaceutical Sciences, University of Southern California, School of Pharmacy, Los Angeles 90033.
  • J S Chang
    Department of Pharmaceutical Sciences, University of Southern California, School of Pharmacy, Los Angeles 90033.
  • S Ohdo
    Department of Pharmaceutical Sciences, University of Southern California, School of Pharmacy, Los Angeles 90033.
  • G M Grass
    Department of Pharmaceutical Sciences, University of Southern California, School of Pharmacy, Los Angeles 90033.
Investigative Ophthalmology & Visual Science October 1991, Vol.32, 2948-2957. doi:
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    • Get Citation

      V H Lee, A M Luo, S Y Li, S K Podder, J S Chang, S Ohdo, G M Grass; Pharmacokinetic basis for nonadditivity of intraocular pressure lowering in timolol combinations.. Invest. Ophthalmol. Vis. Sci. 1991;32(11):2948-2957.

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Abstract

The authors determined whether the ocular absorption of topically applied timolol in the pigmented rabbit was affected significantly by coadministration with either pilocarpine or epinephrine in the same drop to explain the nonadditivity in intraocular pressure lowering (IOP) seen clinically. They instilled 25 microliters of 0.65% timolol maleate solution (equivalent to 0.5% timolol), both in the presence and absence of 2.6% pilocarpine nitrate or 1% epinephrine bitartrate, into pigmented rabbit eyes. The time course of timolol concentration in the conjunctiva, anterior sclera, corneal epithelium, corneal stroma, aqueous humor, iris-ciliary body, and lens was monitored for 360 min by using reversed-phase high-performance liquid chromatography. The area under the timolol concentration-time curve in all but one of the anterior segment tissues was reduced by 20-50% (mean, 40%) when timolol was coadministered with pilocarpine and by 20-70% (mean, 42%) when timolol was coadministered with epinephrine. Such an effect was not a result of alterations in corneal permeability or aqueous humor turnover rate, nor was it related to the extent of systemic absorption caused by pilocarpine and epinephrine. Rather, the reduction in ocular timolol absorption may have been caused by the accelerated washout of timolol by tears stimulated by the coadministered drugs and, to a lesser extent, by the loss of timolol through binding to the increased amount of tear proteins induced by the coadministered drugs. Thus, the nonadditivity in IOP lowering from timolol-pilocarpine and timolol-epinephrine combinations is probably caused by changes in precorneal timolol clearance.

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