title: Ocular Metabolism of Levobunolol: Historic and Emerging Metabolic Pathways.
abstract: 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 β-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.
authors.affiliation: Novartis Institutes for Biomedical Research, Analytical Sciences and Imaging, Cambridge, Massachusetts (U.A.A., J.L.D., C.S., A.L.C., M.G.); and Department of Chemistry, Colorado State University, Fort Collins, Colorado (C.E.D.) upendra.argikar@novartis.com.
authors.forename: Upendra A
authors.initials: UA
authors.lastname: Argikar
authors.affiliation: Novartis Institutes for Biomedical Research, Analytical Sciences and Imaging, Cambridge, Massachusetts (U.A.A., J.L.D., C.S., A.L.C., M.G.); and Department of Chemistry, Colorado State University, Fort Collins, Colorado (C.E.D.).
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Dumouchel
authors.affiliation: Novartis Institutes for Biomedical Research, Analytical Sciences and Imaging, Cambridge, Massachusetts (U.A.A., J.L.D., C.S., A.L.C., M.G.); and Department of Chemistry, Colorado State University, Fort Collins, Colorado (C.E.D.).
authors.forename: Christine E
authors.initials: CE
authors.lastname: Dunne
authors.affiliation: Novartis Institutes for Biomedical Research, Analytical Sciences and Imaging, Cambridge, Massachusetts (U.A.A., J.L.D., C.S., A.L.C., M.G.); and Department of Chemistry, Colorado State University, Fort Collins, Colorado (C.E.D.).
authors.forename: Chitra
authors.initials: C
authors.lastname: Saran
authors.affiliation: Novartis Institutes for Biomedical Research, Analytical Sciences and Imaging, Cambridge, Massachusetts (U.A.A., J.L.D., C.S., A.L.C., M.G.); and Department of Chemistry, Colorado State University, Fort Collins, Colorado (C.E.D.).
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Cirello
authors.affiliation: Novartis Institutes for Biomedical Research, Analytical Sciences and Imaging, Cambridge, Massachusetts (U.A.A., J.L.D., C.S., A.L.C., M.G.); and Department of Chemistry, Colorado State University, Fort Collins, Colorado (C.E.D.).
authors.forename: Mithat
authors.initials: M
authors.lastname: Gunduz
mesh_terms: D000107:Acetylation; D000319:Adrenergic beta-Antagonists / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D005123:Eye / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D002040:Levobunolol / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D015394:Molecular Structure; D009928:Organ Specificity; D011817:Rabbits; D017207:Rats, Sprague-Dawley
chemical_list: D000319:Adrenergic beta-Antagonists; C015810:dihydrobunolol; D002040:Levobunolol