title: Paroxetine markedly increases plasma concentrations of ophthalmic timolol; CYP2D6 inhibitors may increase the risk of cardiovascular adverse effects of 0.5% timolol eye drops.
abstract: Although ophthalmic timolol is generally well tolerated, a significant fraction of topically administered timolol can be systemically absorbed. We investigated the effect of the strong CYP2D6 inhibitor paroxetine on the pharmacokinetics of timolol after ophthalmic administration. In a four-phase crossover study, 12 healthy volunteers ingested either paroxetine (20 mg) or placebo daily for 3 days. In phases 1-2, timolol 0.1% gel, and in phases 3-4, timolol 0.5% drops were administered to both eyes. Paroxetine increased the plasma concentrations of timolol with both timolol formulations to a similar degree. The geometric mean ratio (95% confidence interval) of timolol peak concentration was 1.53-fold (1.23-1.91) with 0.1% timolol and 1.49-fold (0.94-2.36) with 0.5% timolol, and that of timolol area under the plasma concentration-time curve (AUC) from time 0 to 12 hours was 1.61-fold (1.26- to 2.06-fold) and 1.78-fold (1.21-2.62), respectively. During paroxetine administration, six subjects on 0.5% timolol drops, but none on 0.1% timolol gel, had plasma timolol concentrations exceeding 0.7 ng/ml, which can cause systemic adverse effects in patients at risk. There was a positive correlation between the AUC from time 0 to 13 hours of paroxetine and the placebo phase AUC from time 0 to infinity of timolol after timolol 0.5% drops (P < 0.05), and a nonsignificant trend after timolol 0.1% gel, consistent with the role of CYP2D6 in the metabolism of both agents. In the orthostatic test, heart rate immediately after upright standing was significantly lower (P < 0.05) during the paroxetine phase than during the placebo phase at 1 and 3 hours after 0.5% timolol dosing. In conclusion, paroxetine and other CYP2D6 inhibitors can have a clinically important interaction with ophthalmic timolol, particularly when patients are using 0.5% timolol formulations.
authors.affiliation: Santen Oy, Tampere, Finland (J.M., M.V.-M.); Medcare Oy, Äänekoski, Finland (H.K.); and Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland (M.Ne., M.Ni., P.J.N., J.T.B.).
authors.forename: Jukka
authors.initials: J
authors.lastname: Mäenpää
authors.affiliation: Santen Oy, Tampere, Finland (J.M., M.V.-M.); Medcare Oy, Äänekoski, Finland (H.K.); and Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland (M.Ne., M.Ni., P.J.N., J.T.B.).
authors.forename: Marjo
authors.initials: M
authors.lastname: Volotinen-Maja
authors.affiliation: Santen Oy, Tampere, Finland (J.M., M.V.-M.); Medcare Oy, Äänekoski, Finland (H.K.); and Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland (M.Ne., M.Ni., P.J.N., J.T.B.).
authors.forename: Hannu
authors.initials: H
authors.lastname: Kautiainen
authors.affiliation: Santen Oy, Tampere, Finland (J.M., M.V.-M.); Medcare Oy, Äänekoski, Finland (H.K.); and Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland (M.Ne., M.Ni., P.J.N., J.T.B.).
authors.forename: Mikko
authors.initials: M
authors.lastname: Neuvonen
authors.affiliation: Santen Oy, Tampere, Finland (J.M., M.V.-M.); Medcare Oy, Äänekoski, Finland (H.K.); and Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland (M.Ne., M.Ni., P.J.N., J.T.B.).
authors.forename: Mikko
authors.initials: M
authors.lastname: Niemi
authors.affiliation: Santen Oy, Tampere, Finland (J.M., M.V.-M.); Medcare Oy, Äänekoski, Finland (H.K.); and Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland (M.Ne., M.Ni., P.J.N., J.T.B.).
authors.forename: Pertti J
authors.initials: PJ
authors.lastname: Neuvonen
authors.affiliation: Santen Oy, Tampere, Finland (J.M., M.V.-M.); Medcare Oy, Äänekoski, Finland (H.K.); and Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland (M.Ne., M.Ni., P.J.N., J.T.B.) janne.backman@helsinki.fi.
authors.forename: Janne T
authors.initials: JT
authors.lastname: Backman
mesh_terms: D000328:Adult; D019540:Area Under Curve; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D004347:Drug Interactions / Q000502:physiology; D005123:Eye / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D009883:Ophthalmic Solutions / Q000627:therapeutic use*; D017374:Paroxetine / Q000009:adverse effects* / Q000627:therapeutic use; D012306:Risk; D013999:Timolol / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D065690:Cytochrome P-450 CYP2D6 Inhibitors; D009883:Ophthalmic Solutions; D017374:Paroxetine; D013999:Timolol; D019389:Cytochrome P-450 CYP2D6