Timolol metabolism in human liver microsomes is mediated principally by CYP2D6.
Article Details
- CitationCopy to clipboard
Volotinen M, Turpeinen M, Tolonen A, Uusitalo J, Maenpaa J, Pelkonen O
Timolol metabolism in human liver microsomes is mediated principally by CYP2D6.
Drug Metab Dispos. 2007 Jul;35(7):1135-41. doi: 10.1124/dmd.106.012906. Epub 2007 Apr 12.
- PubMed ID
- 17431033 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Timolol Cytochrome P450 2C19 Protein Humans UnknownSubstrateDetails Timolol Cytochrome P450 2D6 Protein Humans UnknownSubstrateDetails - Drug Reactions
Reaction Details - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareTimololMethylene blue The metabolism of Timolol can be decreased when combined with Methylene blue. TimololOritavancin The metabolism of Timolol can be decreased when combined with Oritavancin. TimololEverolimus The metabolism of Timolol can be decreased when combined with Everolimus. TimololViloxazine The metabolism of Timolol can be decreased when combined with Viloxazine. TimololPimozide The metabolism of Timolol can be decreased when combined with Pimozide.
