New information on the pharmacological properties of timolol

Ms. Marjo Volotinen, M.Sc. (Pharm.), from Santen (Finland) successfully defended her doctoral dissertation on ”Expression of cytochrome P450-enzymes and metabolism of timolol in human ocular tissue” at Helsinki University Faculty of Medicine in December 2009. The dissertation, which comprises four original publications, provides a lot of new information on the pharmacological properties of timolol, which will be beneficial when treating patients with Santen Europe products containing timolol.

One of the central observations of the study was that timolol, which is used as an active substance in the following Santen Europe products: Oftan Timolol, Fotil and Timosan, is metabolized in the liver, where it is mainly catalyzed by the cytochrome P450 2D6 (CYP2D6) enzyme. The importance of this finding is highlighted by the fact that the renowned medicines handbook Martindale refers to this study in the section discussing timolol. The study also showed that certain antidepressive medicines, such as fluoxetine and paroxetine, inhibit the metabolism of timolol. Concomitant use of a topical timolol product and such oral substances may lead to an increase in the plasma concentration of timolol.

Congenital glaucoma is associated with mutations in the CYP1B1 gene. The research gave valuable information on the regulation of this gene in the ciliary epithelial cell line. In general, there is little knowledge on the drug-metabolizing CYP enzymes in the eye. This research also gave new information regarding the presence of other CYP enzymes in the ciliary epithelial cells. Based on the results, it is unlikely that timolol would be metabolized in these cells.

In a clinical study conducted with Professor Esko Aine (Tampere University Hospital), the absorption of timolol from the eye surface to the aqueous humor while using Timosan and Oftan Timolol was studied. For the efficacy and safety of medicinal treatment, it is desirable that there are no major differences in the plasma or aqueous humor drug concentrations among patients. This study showed that after administration of Timosan, the inter-individual concentrations of timolol in the aqueous humor are very similar, which gives further evidence of the good qualities of Timosan eye gel.

All four original publications of the thesis were published in recognized international medical journals. Marjo Volotinen collaborated with Oulu University Department of Pharmacology and Toxicology, Novamass Ltd and Tampere University Hospital Clinic of Ophthalmology. The public defense of the dissertation was held on 18 December 2009.

For the dissertation, please see http://urn.fi/URN:ISBN:978-952-10-5883-7

Original publications:

1. Volotinen M et al. Timolol metabolism in human liver microsomes is mediated principally by CYP2D6. Drug Metabolism and Disposition 2007;35:1135-41.

2. Volotinen M et al. Effects of selective serotonin reuptake inhibitors on timolol metabolism in human liver microsomes and cryopreserved hepatocytes. Basic & Clinical Pharmacology & Toxicology. In Press (2010).

3. Volotinen M et al. Expression of cytochrome P450 (CYP) enzymes in human non-pigmented ciliary epithelial cells; induction of CYP1B1 expression by TCDD. Investigative Ophthalmology and Visual Science 2009;50:3099-3105.

4. Volotinen M et al. Ophthalmic timolol in a hydrogel vehicle leads to minor inter-individual variation in timolol concentration in aqueous humor. European Journal of Pharmaceutical Sciences 2009;36:292-6.