Unit of Clinical Pharmacology, L. Sacco University Hospital, Milano, Italy.
Clinical Pharmacology Unit, CNR Institute of Neuroscience, Dept Biomedical and Clinical Sciences, L. Sacco University Hospital, Università di Milano, 20157 Milano, Italy.
Biomed Pharmacother. 2021 Jul;139:111631. doi: 10.1016/j.biopha.2021.111631. Epub 2021 Apr 30.
The exposure to linezolid is characterized by a large inter-individual variability; age, renal dysfunction and body weight explain this variability only to a limited extent and a considerable portion of it remains unexplained; therefore, we decided to investigate the role of individual genetic background focusing in particular on the risk of linezolid underexposure. 191 patients in therapy with linezolid at the standard dose of 600 mg twice daily were considered. Linezolid plasma concentration was determined at the steady state and classified as "below", "within" or "above" reference range. Genetic polymorphisms for ATP Binding Cassette Subfamily B Member 1 (ABCB1), Cytochrome P450 (CYP) enzymes CYP3A4 and CYP3A5, and Cytochrome P450 Oxidoreductase (POR) were investigated. Age significantly correlated with drug exposure, and patients CYP3A5 expressers (GA and AA) were found at high risk to be underexposed to the drug when treated at standard dose. This association was confirmed even after correction with age. No association was found with ABCB1 polymorphism. Our data suggest that CYP3A5 polymorphisms might significantly affect linezolid disposition, putting patients at higher risk to be underexposed, while P-glycoprotein polymorphism seem not to play any role.
利奈唑胺的暴露具有很大的个体间变异性；年龄、肾功能不全和体重仅在一定程度上解释了这种变异性，而且很大一部分仍然无法解释；因此，我们决定研究个体遗传背景的作用，特别是关注利奈唑胺剂量不足的风险。考虑了 191 名接受利奈唑胺标准剂量 600mg 每日两次治疗的患者。在稳态时测定利奈唑胺的血浆浓度，并将其分类为“低于”、“在”或“高于”参考范围。研究了三磷酸腺苷结合盒亚家族 B 成员 1（ABCB1）、细胞色素 P450（CYP）酶 CYP3A4 和 CYP3A5 以及细胞色素 P450 氧化还原酶（POR）的遗传多态性。年龄与药物暴露显著相关，并且在标准剂量治疗时，发现 CYP3A5 表达者（GA 和 AA）的患者存在药物剂量不足的高风险。即使在与年龄校正后，这种关联仍然得到证实。ABCB1 多态性与药物暴露无关。我们的数据表明，CYP3A5 多态性可能显著影响利奈唑胺的处置，使患者面临更高的剂量不足风险，而 P-糖蛋白多态性似乎没有任何作用。
