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An in vitro approach to investigate ocular metabolism: Part II - Betaxolol

Bushee, Jennifer, Dunne, Christine and Argikar, Upendra (2015) An in vitro approach to investigate ocular metabolism: Part II - Betaxolol. Xenobiotica.


Topical glaucoma treatments, including multiple β-adrenergic receptor blocking agents, have often been limited by poor ocular absorption and bioavailability. Betaxolol, a selective β1-blocker, has been well studied for its pharmacokinetics and disposition after oral administration. However, limited betaxolol metabolism has been documented after topical dosage despite the growing number of immediate and sustained release, ocular treatments under investigation to improve absorption and retain efficacy. Conversely, plasma, urine and in vitro liver metabolism data has been reported for other topical glaucoma treatments, for example levobunolol. This investigation developed an ocular S9 assay combined with high-resolution mass spectrometry to investigate the role of ocular metabolism for preclinical and human subcellular fractions. Nine metabolites, eight of which were not previously reported, were characterized. Betaxolol’s active metabolite, hydroxybetaxolol, was observed in rat, rabbit and human ocular and liver S9 fractions. To date, hydroxybetaxolol concentrations in vivo or its binding affinity/selectivity have not been reported. Rabbit liver S9 fractions demonstrated extensive glucuronidation that was not observed ocular fractions. For betaxolol and levobunolol, investigated in a companion paper, the complete ocular metabolic profile could not be predicted from the liver S9 assay alone. This is the first comprehensive report of a functional, in vitro ocular metabolism assay, which demonstrates the poor prediction of ocular metabolism using liver as a surrogate model.

Item Type: Article
Keywords: ocular metabolism
Date Deposited: 26 Apr 2016 23:45
Last Modified: 26 Apr 2016 23:45