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.

In linezolid underexposure, pharmacogenetics matters: The role of CYP3A5 / S. Cheli, M. Fusi, A. De Silvestri, I. Bonini, E. Clementi, D. Cattaneo, C. Montrasio, S. Baldelli. - In: BIOMÉDECINE & PHARMACOTHÉRAPIE. - ISSN 0753-3322. - 139(2021 Jul), pp. 111631.1-111631.7. [10.1016/j.biopha.2021.111631]

In linezolid underexposure, pharmacogenetics matters: The role of CYP3A5

S. Cheli
Primo
;
M. Fusi;A. De Silvestri;E. Clementi;D. Cattaneo;S. Baldelli
Ultimo
2021

Abstract

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.
CYP3A; Linezolid; Pharmacogenetics; Therapeutic drug monitoring; ATP Binding Cassette Transporter, Subfamily B; Adolescent; Adult; Aged; Aged, 80 and over; Aging; Anti-Infective Agents; Cytochrome P-450 CYP3A; Female; Gene Expression Regulation, Enzymologic; Genotype; Humans; Linezolid; Male; Middle Aged; Polymorphism, Genetic; Retrospective Studies; Young Adult; Pharmacogenetics
Settore BIO/14 - Farmacologia
lug-2021
30-apr-2021
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/895604
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