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Drug Metabolism and Disposition Fast Forward
First published on April 12, 2007; DOI: 10.1124/dmd.106.012906

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Received for publication September 19, 2006.
Revised April 11, 2007.
Accepted for publication April 11, 2007.

Timolol metabolism in human liver microsomes is mediated principally by CYP2D6

Marjo Volotinen 1, Miia Turpeinen 2, Ari Tolonen 3, Jouko Uusitalo 4, Jukka Maenpaa 1, Olavi Pelkonen 5*

1 Santen Oy, Tampere, Finland 2 University of Oulu, Dept. of Pharmacology and Toxicology, Oulu, Finland & Novamass Analytical Ltd, O 3 Novamass Analytical Ltd, Oulu, Finland & University of Oulu, Dept. of Chemistry, Oulu, Finland 4 Novamass Analytical Ltd., Oulu, Finland 5 University of Oulu, Dept. of Pharmacology and Toxicology, Oulu, Finland

* Address correspondence to: E-mail: olavi.pelkonen{at}oulu.fi

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 extensively studied. The aim here was to tentatively identify timolol metabolites and to determine the CYP-associated metabolic and interaction properties of timolol in vitro. Four metabolites were identified, the most abundant being a hydroxymetabolite M1. The Km value for the formation of M1 was 23.8 µM in human liver microsomes. Metabolism of timolol with recombinant CYPs 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 Ki value of 0.08 µM. 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 hours, an estimate close to the half-life of about 2-5 hours 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 (≤ 0.2 µg/L), it is suggested that such interaction is of minor clinical relevance.


Key words: CYP2D, cytochrome P450 catalyzed oxidations, human CYP enzymes, liver microsomes, mass spectrometry


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