Abstract
Although ocular transport and delivery have been well studied, the metabolism in the eye is not well-documented, even for clinically available medications such as levobunolol, a potent and non-selective β-adrenergic receptor antagonist. Recently, we reported an in vitro methodology that could be utilized to evaluate ocular metabolism across preclinical species and human. 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. Eleven of the sixteen 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-CYP 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 human in terms of the rate and extent of levobunolol metabolism.
- acetylation/acetyltransferases/NAT
- glucuronidation/UDP-glucuronyltransferases/UGT
- metabolite identification
- reductases
- The American Society for Pharmacology and Experimental Therapeutics