Timolol metabolism in human liver microsomes is mediated principally by CYP2D6.
Timolol has mainly been used topically for the treatment of glaucoma. It has been suggested that the drug is metabolized by cytochrome P450 CYP2D6. The matter has not, however, been extensively studied. The aim here was to tentatively identify timolol metabolites and to determine the P450-associated metabolic and interaction properties of timolol in vitro. Four metabolites were identified, the most abundant being a hydroxy metabolite, M1. The K(m) value for the formation of M1 was 23.8 microM in human liver microsomes. Metabolism of timolol with recombinant P450s and correlation analysis have confirmed the conception that the drug is metabolized principally by CYP2D6, CYP2C19 being only a minor contributor (<10%) to the intrinsic microsomal clearance. The CYP2D6 inhibitor quinidine proved a potent competitive inhibitor of timolol metabolism, with an in vitro K(i) value of 0.08 microM. Fluvoxamine, an inhibitor of CYP2C19, inhibited timolol metabolism to a lesser extent, confirming its minor contribution. Timolol itself did not inhibit CYP2D6-catalyzed dextromethorphan O-demethylation. Judging from the disappearance of timolol in human liver homogenate, the in vivo half-life was extrapolated to be about 3 h, an estimate close to the half-life of about 2 to 5 h observed in vivo. In conclusion, the inhibition of timolol metabolism by quinidine should be taken into account when patients are treated with timolol. However, when plasma timolol concentrations in patients remain low (< or = 0.2 microg/l), it is suggested that such interaction is of minor clinical relevance.
Volotinen
Marjo
M
Santen Oy, Tampere, Finland.
Turpeinen
Miia
M
Tolonen
Ari
A
Uusitalo
Jouko
J
Mäenpää
Jukka
J
Pelkonen
Olavi
O
D000319:Adrenergic beta-Antagonists / Q000737:chemistry / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003640:Dealkylation; D003915:Dextromethorphan / Q000378:metabolism; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016666:Fluvoxamine / Q000494:pharmacology; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008954:Models, Biological; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011802:Quinidine / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry; D013999:Timolol / Q000737:chemistry / Q000378:metabolism*
D000319:Adrenergic beta-Antagonists; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D003915:Dextromethorphan; D013999:Timolol; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D011802:Quinidine; D016666:Fluvoxamine