Ocular Metabolism of Levobunolol

Tang-Liu, Diane; Shackleton, Martha; Richman, Joseph B.

doi:10.1089/jop.1988.4.269

Cited by 13 publications

(4 citation statements)

References 12 publications

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“…Reduction of LB to M11 has been reported to occur in cytosol, but not microsomes, and is NADPH- (Lee et al, 1988) and pH-dependent (Tang-Liu et al, 1988). Overall, the literature hints at a possible liver cytosolic role (Leinweber et al, 1972) and an even weaker role of an unknown enzyme system in rat and human erythrocytes (Leinweber and Di Carlo, 1974).…”

Section: Discussionmentioning

confidence: 99%

Ocular Metabolism of Levobunolol: Historic and Emerging Metabolic Pathways

Argikar

Dumouchel

Dunne

et al. 2016

Drug Metabolism and Disposition

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Although ocular transport and delivery have been well studied, metabolism in the eye is not well documented, even for clinically available medications such as levobunolol, a potent and nonselective b-adrenergic receptor antagonist. Recently, we reported an in vitro methodology that could be used to evaluate ocular metabolism across preclinical species and humans. The current investigation provides detailed in vitro ocular and liver metabolism of levobunolol in rat, rabbit, and human S9 fractions, including the formation of equipotent active metabolite, dihydrolevobunolol, with the help of high-resolution mass spectrometry. 11 of the 16 metabolites of levobunolol identified herein, including a direct acetyl conjugate of levobunolol observed in all ocular and liver fractions, have not been reported in the literature. The study documents the identification of six human ocular metabolites that have never been reported. The current investigation presents evidence for ocular and hepatic metabolism of levobunolol via non-cytochrome P450 pathways, which have not been comprehensively investigated to date. Our results indicated that rat liver S9 and human ocular S9 fractions formed the most metabolites. Furthermore, liver was a poor in vitro surrogate for eye, and rat and rabbit were poor surrogates for human in terms of the rate and extent of levobunolol metabolism.

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Section: Discussionmentioning

confidence: 99%

Ocular Metabolism of Levobunolol: Historic and Emerging Metabolic Pathways

Argikar

Dumouchel

Dunne

et al. 2016

Drug Metabolism and Disposition

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“…The total concentration of levobunolol and dihydrobunolol in ocular tissues is in the micromolar range. DHLB is the major breakdown product of levobunolol in the cornea, aqueous humour, and iris-ciliary body [82]. Topically applied 0.001 and 0.01% DHLB virtually abolished the response to isoproterenol, indicating a b-blocking potency similar to that of timolol.…”

Section: Levobunololmentioning

confidence: 96%

Pharmacotherapy of intraocular pressure: part I. Parasympathomimetic, sympathomimetic and sympatholytics

Costagliola

dell’Omo

Romano

et al. 2009

Expert Opinion on Pharmacotherapy

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Elevated intraocular pressure (IOP) has been recognized as the major risk factor for the development of glaucoma and a wide range of options are now available to reduce it: medical treatment, laser, filtering, or cyclodestructive surgery (alone or in combination). All these modalities act by decreasing eye pressure and, thereby, protecting the optic nerve head from a mechanic direct and/or vascular indirect insult. Topical medical therapy represents the first-choice treatment and, in most cases, it effectively controls IOP, avoiding the occurrence of further optic nerve damage. All medications lower IOP in two main ways: decreasing the production of aqueous humour or by increasing its outflow from the eye. Consequently, antiglaucoma drugs either suppress aqueous humour formation (beta-adrenergic antagonists, carbonic anhydrase inhibitors, and alpha-2-adrenergic agonists) or raise aqueous humour outflow throughout the conventional (e.g., pilocarpine) or uveoscleral (prostaglandin FP receptor agonists, and prostamides) route. In addition, fixed and unfixed combinations of antiglaucoma compounds have also been available for patients requiring more than one type of medication. This review, which is part one of two (please see Expert Opinion on Pharmacotherapy 10 (17)) briefly considers the characteristics of sympathomimetic, sympatholytics and parasympathomimetic commonly employed in the medical treatment of glaucoma, mainly the primary open-angle form, focusing the discussion on the clinical evidence supporting the use of these three classes of compound.

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“…3,4,8,10 To date, a number of endogenous molecules, biochemical probes, and clinically used drugs have been reported to undergo metabolism in the eye. Tryptamine, 11 fluorescein, [12][13][14] p-amino salicylic acid, 15chloramphenicol, 16 betaxolol, 17 levobunolol, [18][19][20] ractopamine, 21 sulindac, 16 and morphine 22 are just a few examples. In vitro ocular metabolic pathways of clinically used topical b-blockers like betaxolol and levobunolol were comprehensively compared across rat, rabbit, and human.…”

Section: Drug Disposition In the Eyementioning

confidence: 99%

Do We Need to Study Metabolism and Distribution in the Eye: Why, When, and Are We There Yet?

Argikar¹,

Dumouchel²,

Kramlinger³

et al. 2017

Journal of Pharmaceutical Sciences

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The liver is known to be the principal site of drug metabolism. Depending on the route of administration, especially in cases of topical and local delivery, evaluation of local drug metabolism in extrahepatic tissues is vital to assess fraction of the drug metabolized. This parameter becomes important from the point of view of drug availability or the contribution to overall clearance. Examples include fraction metabolized in the gut for oral drugs and contribution of pulmonary or renal clearance to total clearance of a drug. Diseases of the eye represent a rising unmet medical need and a number of therapeutics are currently being developed in the form of small molecules and biologics. Treatment of ocular diseases has expanded to explore various topical formulations and local short- and long-term therapies by ocular routes of administration. Until recently, metabolism in the eye for any species, including human, was not well documented, but this topic is gaining wide interest. Many in vitro-ex vivo models, each with separate pros and cons, are being used for studying ocular metabolism. This review is aimed at providing a perspective on the relevance and application of ocular metabolism, melanin binding, and the use of tissue- and cell-derived ocular models in discovery and preclinical development.

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Ocular Metabolism of Levobunolol

Cited by 13 publications

References 12 publications

Ocular Metabolism of Levobunolol: Historic and Emerging Metabolic Pathways

Ocular Metabolism of Levobunolol: Historic and Emerging Metabolic Pathways

Pharmacotherapy of intraocular pressure: part I. Parasympathomimetic, sympathomimetic and sympatholytics

Do We Need to Study Metabolism and Distribution in the Eye: Why, When, and Are We There Yet?

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