Institute of Biomedicine, Pharmacology, University of Helsinki, Finland.
Basic Clin Pharmacol Toxicol. 2011 May;108(5):297-303. doi: 10.1111/j.1742-7843.2011.00694.x.
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 β-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.
青光眼是一种常见的眼部疾病，如果在进展的早期阶段没有被诊断和治疗，可能会导致不可逆转的失明。这种疾病通常（尽管并非总是如此）与眼内压升高有关，而眼内压升高也是青光眼的最重要的危险因素。目前，青光眼的唯一治疗选择是降低眼内压。β-肾上腺素能拮抗剂噻吗洛尔已被用于治疗青光眼和眼压升高超过 30 年，仍然是首选药物。局部使用噻吗洛尔耐受性良好。然而，据报道，大约 80%的局部滴眼剂被全身吸收。因此，眼部使用噻吗洛尔可能会引起严重的心血管和呼吸系统不良反应。鉴于上述情况，令人有些惊讶的是，尽管该药物已使用了几十年，但噻吗洛尔的代谢仅在最近才被详细研究。早期的临床研究表明，噻吗洛尔是由细胞色素 P450 家族的重要成员 CYP2D6 代谢的。我们最近的体外研究令人信服地表明，CYP2D6 是导致噻吗洛尔代谢的主要酶，尽管 CYP2C19 也可能有较小的作用。肝脏是噻吗洛尔代谢的主要部位，因为根据我们最近的发现，人类眼部组织中只有微不足道的 CYP2D6 表达。局部给药后，全身噻吗洛尔浓度可能足够高，导致心血管和呼吸系统不良反应，特别是在 CYP2D6 弱代谢者或同时使用 CYP2D6 抑制剂的患者中。
