Pharmacogenetic Explanation for Excessive β-Blockade Following Timolol Eye Drops

Progress toward personalized medicine for glaucoma

“…This drug class is metabolized by the cytochrome P450 enzyme, CYP2D6, which has been extensively studied for sequence variants of the gene having functional consequences on drug metabolism [69]. A small, prospective clinical trial showed that excessive β-blockade of heart rate and higher plasma timolol concentration occurred in subjects who were genotyped as CYP2D6-poor metabolizers compared with those who were CYP2D6-extensive metabolizers [70]. …”

Pharmacogenetics of timolol

“…В исследовании T. Edeki и соавт. [46] 8 здоровым добровольцам глазные капли 0,5% тимолола малеата вводили интраназально, а не инстиллировали в глаза. Чтобы уменьшить вариабельность между дозами вводили строго по 2 капли в ноздрю.…”

Potential therapeutic hazards due to drug–drug interaction between topically and systemically coadministered medications

“…Some factors may influence the likelihood of DDI between topically and systemically administered medications and they are as follows: (1) percentage of body surface area to which the topical formulation is applied; (2) age of the patient – the very old and very young are more likely to exhibit DDI; (3) genetic factors may affect the magnitude of DDI (eg, DDI between timolol eye drops and oral quinidine is dependent on CYP2D6 phenotype; poor metabolizers have a higher risk for DDIs with a low systemic concentration of a topical imidazole derivative than extensive metabolizers do);5,17 (4) method of application-medications applied under occlusion are more likely to cause DDI; (5) condition of the stratum corneum-topical formulations applied to mucous membranes, genital skin, or thin, macerated or ulcerated skin are more susceptible to be systemically absorbed; and (6) other concomitantly used medications are also involved in the DDI mechanism, eg, topical terbinafine (precipitant drug) impaired CYP2D6-mediated drug metabolism of diltiazem and elevated diltiazem level increased the magnitude of CYP3A4-mediated metabolism inhibition toward acenocoumarol (object drug) 9…”