Metabolism of ophthalmic timolol: new aspects of an old drug.

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Volotinen M, Hakkola J, Pelkonen O, Vapaatalo H, Maenpaa J

Metabolism of ophthalmic timolol: new aspects of an old drug.

Basic Clin Pharmacol Toxicol. 2011 May;108(5):297-303. doi: 10.1111/j.1742-7843.2011.00694.x.

PubMed ID

21385322 [ View in PubMed

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Abstract

Glaucoma is a common eye disease that can cause irreversible blindness if not diagnosed and treated in the early stages of progression. This disease is often, albeit not always, associated with increased intraocular pressure, which is also the most important risk factor for glaucoma. Currently, the only treatment option of glaucoma is reduction of intraocular pressure. A beta-adrenergic antagonist, timolol, has been used for the treatment of glaucoma and increased intraocular pressure for more than 30 years and still remains the drug of choice. Locally, timolol is well tolerated. However, it has been reported that approximately 80% of a topically administered eye drop is systemically absorbed. Thus, ophthalmic timolol may cause severe adverse cardiovascular and respiratory effects. On the basis of the aforementioned situation, it is somewhat surprising to notice that the metabolism of timolol has only recently been studied in detail even though the drug has been used for decades. Earlier clinical studies have suggested that timolol is metabolized by CYP2D6, an important member of the cytochrome P450 family. Our recent in vitro studies demonstrated convincingly that CYP2D6 is the main enzyme contributing to timolol metabolism, although also CYP2C19 may have a minor role. Liver is the principal site of timolol metabolism, because - according to our recent findings - only negligible amounts of CYP2D6 are expressed in human ocular tissues. After topical administration, systemic timolol concentrations may be high enough to cause cardiovascular and respiratory adverse effects especially in patients who are CYP2D6 poor metabolizers or use concomitant CYP2D6 inhibitors.

DrugBank Data that Cites this Article

Drugs

Timolol

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Timolol	Cytochrome P450 2C19	Protein	Humans	Unknown	Substrate	Details

Drug Reactions

Reaction
Timolol DB00373 Cytochrome P450 2D6 Cytochrome P450 2C19 M1 metabolite, timolol DBMET02575	Details

Pharmaco-genomics

Drug	Interacting Gene/Enzyme	Allele name	Genotypes	Defining change(s)	Type(s)	Description	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*3	Not Available	C allele (rs35742686)	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*4	Not Available	C allele (rs3892097)	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*5	Not Available	Whole-gene deletion	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*6	Not Available	1707delT (rs5030655)	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*7	Not Available	2935A>C (rs5030867)	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*8	Not Available	1758G>T (rs5030865)	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*11	Not Available	883G>C (rs5030863)	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*12	Not Available	124G>A (rs5030862)	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*13	Not Available	CYP2D7/2D6 hybrid gene structure	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*14A	Not Available	1758G>A (rs5030865)	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*15	Not Available	137insT, 137_138insT	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*19	Not Available	2539_2542delAACT (rs72549353)	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*20	Not Available	1973_1974insG (rs72549354)	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*21	Not Available	2573insC	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*31	Not Available	-1770G>A -1584C>G -1235A>G show all 17 …	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*36	Not Available	100C>T (rs1065852) -1426C>T variable number of A’s in the region -1258 to -1237a show all 9 …	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*38	Not Available	2587_2590delGACT (rs72549351)	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*40	Not Available	1863_1864ins(TTT CGC CCC)2 (rs72549356)	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*42	Not Available	3259_3260insGT (rs72549346)	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*44	Not Available	2950G>C	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*47	Not Available	100C>T (rs1065852) -1426C>T -1235A>G show all 8 …	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*51	Not Available	-1584C>G -1235A>G -740C>T show all 9 …	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*56	Not Available	3201C>T (rs72549347)	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*57	Not Available	100C>T 310G>T 843T>G show all 10 …	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*62	Not Available	4044C>T	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*68A	Not Available	-1426C>T -1235A>G -1000G>A show all 6 …	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*68B	Not Available	Similar but not identical switch region compared to CYP2D668A. Found in tandem arrangement with CYP2D64.	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*69	Not Available	2988G>A (rs28371725) -1426C>T -1235A>G show all 17 …	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*92	Not Available	1995delC	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*100	Not Available	-1426C>T -1235A>G -1109C>T show all 15 …	Effect Inferred	Poor drug metabolizer.	Details
Timolol	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*101	Not Available	-1426C>T -1235A>G -1000G>A show all 14 …	Effect Inferred	Poor drug metabolizer.	Details