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

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...

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Published in:Basic & clinical pharmacology & toxicology 2018-05, Vol.122 (5), p.501-511
Main 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
Format: Article
Language:English
Subjects:
Administration, Oral
Adolescent
Adult
Alleles
Antidepressants
Blood pressure
Blood Pressure - drug effects
CYP2D6 protein
Cytochrome
Cytochrome P-450 CYP2B6 - genetics
Cytochrome P-450 CYP2B6 - metabolism
Cytochrome P-450 CYP2C19 - genetics
Cytochrome P-450 CYP2C19 - metabolism
Cytochrome P450
Enzymes
Female
Genes
Genetic diversity
Genetic variance
Genotype
Glycoproteins
Healthy Volunteers
Heart rate
Heart Rate - drug effects
Humans
Liver
Male
Middle Aged
Pharmacodynamics
Pharmacogenetics
Pharmacogenomic Variants
Pharmacokinetics
Pharmacology
Phenotype
Polymorphism, Single Nucleotide
Pressure effects
Receptors
Risk Assessment
Safety
Serotonin
Serotonin receptors
Serotonin uptake inhibitors
Serotonin Uptake Inhibitors - administration & dosage
Serotonin Uptake Inhibitors - adverse effects
Serotonin Uptake Inhibitors - pharmacokinetics
Sertraline
Sertraline - administration & dosage
Sertraline - adverse effects
Sertraline - pharmacokinetics
Side effects
Substrates
Women
Young Adult
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Summary: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.
ISSN:1742-7835
1742-7843
DOI:10.1111/bcpt.12938