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

Basic Clin Pharmacol Toxicol. 2018 May;122(5):501-511. doi: 10.1111/bcpt.12938. Epub 2017 Dec 13.

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 (CYP2B6, CYP2C9, CYP2C19, CYP2D6), ATP-binding cassette subfamily B member 1 (ABCB1), solute carrier family 6 member 4 (SLC6A4), 5-hydroxytryptamine receptor 2A (HTR2A) and 5-hydroxytryptamine receptor 2C (HTR2C) genes. Pharmacokinetic and pharmacodynamic parameters were similar in men and women. Polymorphisms in CYP2C19 and CYP2B6 genes influenced sertraline pharmacokinetics, with a greater effect of CYP2C19. Individuals carrying defective alleles for CYP2C19 and CYP2B6 showed higher area under the curve (AUC) and half-life (T1/2 ). Moreover, CYP2C19*17 was related to a decreased AUC and T1/2 . No significant effect was found for polymorphisms in CYP2C9, CYP2D6 and ABCB1 on sertraline pharmacokinetics. Sertraline had a small heart rate-lowering effect, directly related to maximum concentration (Cmax ) and the presence of ABCB1 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 CYP2C19 intermediate metabolizers and CYP2B6 G516T T/T individuals.

Publication types

  • Comparative Study
  • Randomized Controlled Trial

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Blood Pressure / drug effects
  • Cytochrome P-450 CYP2B6 / genetics*
  • Cytochrome P-450 CYP2B6 / metabolism
  • Cytochrome P-450 CYP2C19 / genetics*
  • Cytochrome P-450 CYP2C19 / metabolism
  • Female
  • Genotype
  • Healthy Volunteers
  • Heart Rate / drug effects
  • Humans
  • Male
  • Middle Aged
  • Pharmacogenetics
  • Pharmacogenomic Variants*
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Risk Assessment
  • Selective Serotonin Reuptake Inhibitors / administration & dosage
  • Selective Serotonin Reuptake Inhibitors / adverse effects
  • Selective Serotonin Reuptake Inhibitors / pharmacokinetics*
  • Sertraline / administration & dosage
  • Sertraline / adverse effects
  • Sertraline / pharmacokinetics*
  • Young Adult

Substances

  • Serotonin Uptake Inhibitors
  • CYP2B6 protein, human
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP2C19
  • Sertraline