Effect of Polymorphisms on the Pharmacokinetics, Pharmacodynamics and Safety of Sertraline in Healthy Volunteers

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 ( CYP 2B6 , CYP 2C9 , CYP 2C19 , CYP 2D6 ) , ATP ‐binding cassette subfamily B member 1 ( ABCB 1 ), solute carrier family 6 member 4 ( SLC 6A4 ), 5‐hydroxytryptamine receptor 2A ( HTR 2A ) and 5‐hydroxytryptamine receptor 2C ( HTR 2C ) genes. Pharmacokinetic and pharmacodynamic parameters were similar in men and women. Polymorphisms in CYP 2C19 and CYP 2B6 genes influenced sertraline pharmacokinetics, with a greater effect of CYP 2C19 . Individuals carrying defective alleles for CYP 2C19 and CYP 2B6 showed higher area under the curve ( AUC ) and half‐life ( T 1/2 ). Moreover, CYP 2C19*17 was related to a decreased AUC and T 1/2 . No significant effect was found for polymorphisms in CYP 2C9 , CYP 2D6 and ABCB 1 on sertraline pharmacokinetics. Sertraline had a small heart rate‐lowering effect, directly related to maximum concentration ( C max ) and the presence of ABCB 1 minor alleles. Sertraline had no significant effect on blood pressure and QT c. There was a tendency to present more adverse drug reactions in women and individuals with higher AUC of sertraline, such as CYP 2C19 intermediate metabolizers and CYP 2B6 G516T T/T individuals.