Effects of Selective Serotonin Reuptake Inhibitors on Timolol Metabolism in Human Liver Microsomes and Cryo-Preserved Hepatocytes
Marjo Volotinen
Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland
Santen Oy, Tampere, Finland
Search for more papers by this authorMiia Turpeinen
Novamass Ltd, Oulu, Finland
Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland
Search for more papers by this authorOlavi Pelkonen
Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland
Search for more papers by this authorJukka Hakkola
Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland
Search for more papers by this authorMarjo Volotinen
Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland
Santen Oy, Tampere, Finland
Search for more papers by this authorMiia Turpeinen
Novamass Ltd, Oulu, Finland
Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland
Search for more papers by this authorOlavi Pelkonen
Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland
Search for more papers by this authorJukka Hakkola
Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland
Search for more papers by this authorAbstract
Abstract: Timolol has been widely used in the treatment of glaucoma. Topically applied, timolol may cause adverse cardiovascular effects due to systemic absorption through the nasolacrimal duct. Timolol is mainly metabolized by cytochrome P450 2D6 (CYP2D6) in the liver. The aim of the present study was to characterize further the metabolism of timolol in vitro. Especially the effect of several drugs such as selective serotonin reuptake inhibitors on the metabolism of timolol was evaluated. In human liver microsomes, four timolol metabolites were identified, in cryo-preserved hepatocytes nine. In both in vitro experiments, the hydroxy metabolite M1 was the main metabolite. The in vivo half-life predicted for timolol was 3.7 hr. in cryo-preserved hepatocytes, corresponding to the half-life of timolol in humans in vivo. Fluoxetine, paroxetine, sertraline, citalopram and fluvoxamine inhibited the formation of M1 in microsomes with IC50 values of 1.4, 2.0, 3.5, 21 and 20 μM, respectively. In human cryo-preserved hepatocytes, the IC50 values for fluoxetine, paroxetine and fluvoxamine were 0.7, 0.5 and 5.9 μM, respectively. In conclusion, compounds known to be potent CYP2D6 inhibitors inhibited timolol metabolism in in vitro experiments. The present results strongly suggest that fluoxetine and paroxetine may significantly affect the metabolism of timolol also in vivo and may thus potentiate the adverse cardiovascular effects of topically administered timolol.
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