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- Title
Effect of Polymorphisms on the Pharmacokinetics, Pharmacodynamics and Safety of Sertraline in Healthy Volunteers.
- Authors
Saiz‐Rodríguez, Miriam; Belmonte, Carmen; Román, Manuel; Ochoa, Dolores; Koller, Dora; Talegón, María; Ovejero‐Benito, María C.; López‐Rodríguez, Rosario; Cabaleiro, Teresa; Abad‐Santos, Francisco
- Abstract
Abstract: Sertraline is a selective serotonin reuptake inhibitor widely metabolized in the liver by cytochrome P450 (CYP) enzymes. Besides, it is a P‐glycoprotein substrate. Moreover, serotonin transporters and serotonin receptors are involved in its efficacy and safety. The aim of this study was to evaluate the role of polymorphisms of metabolizing enzymes, transporters and receptors on the pharmacokinetics, pharmacodynamics and tolerability of sertraline in healthy volunteers. Forty‐six healthy volunteers (24 men and 22 women) receiving a 100‐mg single oral dose of sertraline were genotyped for 17 genetic variants of CYP enzymes (<italic>CYP2B6</italic>,<italic> CYP2C9</italic>,<italic> CYP2C19</italic>,<italic> CYP2D6</italic>)<italic>, </italic>ATP‐binding cassette subfamily B member 1 (<italic>ABCB1</italic>), solute carrier family 6 member 4 (<italic>SLC6A4</italic>), 5‐hydroxytryptamine receptor 2A (<italic>HTR2A</italic>) and 5‐hydroxytryptamine receptor 2C (<italic>HTR2C</italic>) genes. Pharmacokinetic and pharmacodynamic parameters were similar in men and women. Polymorphisms in <italic>CYP2C19</italic> and <italic>CYP2B6</italic> genes influenced sertraline pharmacokinetics, with a greater effect of <italic>CYP2C19</italic>. Individuals carrying defective alleles for <italic>CYP2C19</italic> and <italic>CYP2B6</italic> showed higher area under the curve (AUC) and half‐life (<italic>T</italic>1/2). Moreover, <italic>CYP2C19*17</italic> was related to a decreased AUC and <italic>T</italic>1/2. No significant effect was found for polymorphisms in <italic>CYP2C9</italic>,<italic> CYP2D6</italic> and <italic>ABCB1</italic> on sertraline pharmacokinetics. Sertraline had a small heart rate‐lowering effect, directly related to maximum concentration (<italic>C</italic>max) and the presence of <italic>ABCB1</italic> minor alleles. Sertraline had no significant effect on blood pressure and QTc. There was a tendency to present more adverse drug reactions in women and individuals with higher AUC of sertraline, such as <italic>CYP2C19</italic> intermediate metabolizers and <italic>CYP2B6</italic> G516T T/T individuals.
- Subjects
GENETIC polymorphisms; PHARMACODYNAMICS; DRUG metabolism; CYTOCHROME P-450; SEROTONIN uptake inhibitors
- Publication
Basic & Clinical Pharmacology & Toxicology, 2018, Vol 122, Issue 5, p501
- ISSN
1742-7835
- Publication type
Article
- DOI
10.1111/bcpt.12938