Sertraline

CYP2C19 Polymorphisms and Enzyme Activity (e.g., *1, *2, *3, *17 alleles)

The CYP2C19 gene is highly polymorphic, with numerous allelic variants affecting enzyme function mdpi.comcpicpgx.org. Key alleles include the normal function CYP2C191, the no-function alleles CYP2C192 and CYP2C193, and the increased-function allele CYP2C1917 cpicpgx.orgnih.govresearchgate.net. These variants lead to different metabolizer phenotypes, including poor metabolizers (PMs), intermediate metabolizers (IMs), normal metabolizers (NMs), and ultrarapid metabolizers (UMs) nih.gov.

CYP2C19*1: Represents the reference allele associated with normal enzyme function. researchgate.net

CYP2C19*2 and *3: These are common no-function alleles that result in greatly reduced or absent enzyme activity. cpicpgx.orgnih.govresearchgate.net

CYP2C19*17: This allele is located in the promoter region and leads to increased gene transcription and, consequently, increased metabolic capacity. cpicpgx.orgnih.govresearchgate.net

The distribution of these alleles and resulting phenotypes can vary significantly among different populations researchgate.net.

Impact on this compound Plasma Levels and Dose Titration

CYP2C19 polymorphisms have a notable impact on this compound plasma concentrations. Individuals who are CYP2C19 PMs (carrying two no-function alleles like *2 or *3) exhibit significantly slower metabolism of this compound, leading to increased exposure to the parent compound nih.govresearchgate.net. Studies have shown that PMs can have significantly higher serum concentrations of this compound compared to NMs nih.govresearchgate.net. For instance, PMs and IMs have shown 2.68- and 1.38-fold higher this compound serum concentrations, respectively, compared to NMs in one study nih.gov.

Conversely, individuals with increased CYP2C19 activity, such as UMs (carrying two CYP2C1917 alleles), might have lower plasma concentrations due to increased metabolism nih.govresearchgate.net. However, some studies suggest that the CYP2C1917 allele may only have a marginal effect on this compound plasma concentrations compared to its impact on other SSRIs like escitalopram nih.govnih.gov.

The influence of CYP2C19 genotype on this compound metabolism suggests that dose adjustments may be necessary to achieve similar plasma concentrations across different metabolizer phenotypes nih.govresearchgate.net. Modeling studies indicate that PMs may require lower doses to achieve exposure comparable to NMs, while UMs might require higher doses nih.govresearchgate.net.

Clinical Guidelines for CYP2C19 Poor Metabolizers

Recognizing the impact of CYP2C19 genotype on this compound pharmacokinetics and the potential for increased side effects in PMs, clinical guidelines have been developed nih.govnih.gov. The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends considering a 50% reduction in the recommended starting dose for CYP2C19 PMs and titrating based on response, or selecting an alternative antidepressant not primarily metabolized by CYP2C19 nih.govpharmgkb.org. The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) also recommends lower doses for CYP2C19 PMs, suggesting that doses should not exceed 75 mg/day and should be guided by response, side effects, and/or plasma concentration pharmgkb.org.

Here is a summary of dosing considerations based on CYP2C19 phenotype:

Note: These are general recommendations based on guidelines and may vary. Other clinical factors should also be considered. pharmgkb.orgpharmgkb.org

CYP2C9 Polymorphisms and this compound Pharmacokinetics

CYP2C9 is another enzyme involved in drug metabolism and exhibits genetic polymorphisms mdpi.com. However, studies investigating the effect of CYP2C9 alleles on this compound pharmacokinetics have generally found no significant impact nih.govresearchgate.netcsic.es.

ABCB1 Gene Variants (e.g., rs2235040, rs2032583) and Adverse Effects

The ABCB1 gene encodes P-glycoprotein (P-gp), an efflux pump located at the blood-brain barrier that can influence the concentration of drugs in the brain researchgate.netpharmgkb.org. This compound is a substrate of P-gp researchgate.netnih.gov. Genetic variants in ABCB1 have been investigated for their association with this compound response and adverse effects.

Some studies have found associations between specific ABCB1 gene variants and adverse effects related to SSRI treatment, including this compound. The A allele of rs2235040 and the C allele of rs2032583 in ABCB1 have been associated with increased adverse effects, particularly serotonergic side effects such as diarrhea or nausea, and SSRI-related insomnia nih.govresearchgate.netpharmgkb.org. The T allele of rs2235040 has been associated with an increased likelihood of adverse effects when treated with several SSRIs, including this compound, in individuals with Major Depressive Disorder pharmgkb.org. Similarly, rs2032583 has been linked to SSRI-related adverse drug effects researchgate.netpharmgkb.org.

However, other research has not consistently found an association between these ABCB1 variants and SSRI side effects or dose/plasma concentrations nih.gov. While some studies suggest an association between ABCB1 variants and side effects or time to remission in patients taking this compound, the exact mechanism remains unclear, and conflicting findings exist regarding the impact of ABCB1 variants on this compound clearance nih.govresearchgate.net.

Serotonin Transporter Gene (SLC6A4) Polymorphisms (e.g., VNTR, predicted expression levels)

The SLC6A4 gene, located on chromosome 17, is central to this compound's mechanism of action as it encodes the serotonin transporter. This gene exhibits several polymorphic variations, including a well-studied insertion/deletion polymorphism in the promoter region known as 5-HTTLPR, and a variable number tandem repeat (VNTR) in intron 2 (STin2). csic.esmedscape.com The 5-HTTLPR polymorphism, characterized by a 44-bp insertion or deletion, results in a long (L) or short (S) allele. medscape.com The L allele is generally associated with higher transcriptional efficiency and thus greater expression of the serotonin transporter compared to the S allele. medscape.com The VNTR region in intron 2 involves 9-12 repeats of a 16/17 base pair unit and appears to regulate transcriptional efficiency. csic.es

Association with this compound Response and Duration of Treatment

Studies have investigated the association between SLC6A4 polymorphisms and this compound response. Some research indicates that patients homozygous for the 5-HTTLPR long allele may show an improved response to this compound compared to those with one or two copies of the short allele. nih.govpharmgkb.org However, these findings have not been consistently replicated across all studies. nih.govpharmgkb.org Regarding the VNTR in SLC6A4, one study found no association between this polymorphism and this compound response. nih.govpharmgkb.org

An association has been observed between predicted expression levels of SLC6A4 and the duration of treatment with this compound. nih.govresearchgate.net Specifically, a decrease in the expression of SLC6A4 has been indicated to prolong the treatment course in patients. researchgate.net

Serotonin Receptor Genes (HTR1A, HTR2A) Variants (e.g., rs6311, rs6313, rs7997012)

Serotonin receptors, particularly 5-HT1A (encoded by HTR1A) and 5-HT2A (encoded by HTR2A), are key components of the serotonergic system and are involved in the downstream effects of increased synaptic serotonin levels resulting from this compound treatment. Polymorphisms in these receptor genes can influence signaling cascades and potentially impact treatment response and side effect profiles.

The HTR2A gene, located on chromosome 13, contains several variants that have been studied in relation to antidepressant response. psychiatryonline.org Two such variants are rs6311 (also known as 1438A/G) and rs6313 (also known as 102T/C), which are in complete linkage disequilibrium. tandfonline.com Another variant is rs7997012. mdpi.comresearchgate.net

Association with this compound Response and Side Effects

Polymorphisms in serotonin receptor genes have been associated with response or remission to SSRI drugs, including this compound. csic.es Some studies suggest that certain HTR2A polymorphisms, such as rs3803189 and rs7997012, may be associated with better response to SSRIs. mdpi.comresearchgate.net Conversely, other studies have not found a significant link between various HTR2A polymorphisms and antidepressant treatment response. mdpi.comresearchgate.net

Regarding side effects, limited data exist on the specific association of HTR2A variants with this compound-related adverse events. A study examining HTR2A variants rs6311 and rs6313 found no association between either SNP and this compound-induced nausea and vomiting. nih.govpharmgkb.org However, some research suggests that specific HTR2A polymorphisms, including rs7997012 and rs6314, might be linked to a reduced risk of antidepressant adverse effects. mdpi.comresearchgate.net

The role of HTR1A polymorphisms in response to antidepressant therapy has also been investigated, with some recent studies finding no significant associations. mdpi.comresearchgate.net However, other studies have reported different findings, suggesting potential associations between HTR1A variants and response to certain SSRIs. mdpi.comresearchgate.net

GRIK4 and ACE Gene Variants

Genetic variants in genes other than those directly involved in serotonin transport and receptors have also been explored for their potential influence on this compound response. These include genes like GRIK4 and ACE.

GRIK4 encodes a subunit of the kainate receptor, a type of glutamate receptor. Glutamatergic neurotransmission is known to interact with the serotonergic system and may play a role in the pathophysiology of depression and the response to antidepressants. An association between the rs1954787 variant in GRIK4 and response to antidepressants, including this compound, has been reported in some studies. nih.govpharmgkb.org The CC genotype of rs1954787 in GRIK4 has been associated with increased response to antidepressants in individuals with major depressive disorder compared to the CT or TT genotypes. pharmgkb.org

The ACE gene encodes the angiotensin-converting enzyme, which is involved in the renin-angiotensin system. While primarily known for its role in blood pressure regulation, components of this system are also present in the brain and may influence mood and response to psychiatric treatment. An association between the deletion allele of rs1799752 in ACE and improved this compound response has been reported. nih.govpharmgkb.org This deletion allele is linked to increased plasma levels of ACE. nih.govpharmgkb.org

GNB3 Gene Variants (e.g., rs45476395) and Treatment Response

The GNB3 gene encodes the G protein β3 subunit, which is involved in intracellular signaling pathways activated by G protein-coupled receptors, including some serotonin receptors. Variants in GNB3 may therefore affect signaling cascades relevant to major depressive disorder or the physiological response to this compound.

The GG genotype of rs45476395 in GNB3 has been associated with an improved response to this compound in patients with major depressive disorder. nih.govpharmgkb.org However, another study did not find an association between rs5441 in GNB3 and response to this compound. nih.govpharmgkb.org

Compound Names and PubChem CIDs

Data Tables

Based on the search results, here is a summary of some of the reported associations:

HLA Alleles and Drug-Induced Liver Injury

Drug-induced liver injury (DILI) is a rare but potentially severe adverse effect associated with various medications, including antidepressants like this compound. While the precise mechanisms underlying this compound-induced DILI are not fully understood, genetic factors, particularly variations in human leukocyte antigen (HLA) alleles, have been investigated for their potential role in increasing susceptibility.

Research, including genome-wide association studies (GWAS), has aimed to identify genetic risk factors for DILI from various drugs. One notable finding from a GWAS involving individuals of European descent with DILI identified an association between the HLA class I allele HLA-A33:01 and DILI. This association was validated for DILI induced by several drugs, including this compound. researchgate.netnih.govworktribe.comresearchgate.netpharmgkb.org The HLA-A33:01 allele was found to have an allele frequency of 0.01 in Caucasian controls and 0.02 in DILI patients in one study. nih.gov Specifically, in a subset of 5 cases of DILI attributed to this compound, HLA-A*33:01 was present in 2 cases. nih.gov

The involvement of specific HLA alleles in DILI suggests a potential immune-mediated component to the liver injury. worktribe.comjournals.co.zaresearchgate.netresearchgate.net HLA molecules play a crucial role in presenting antigens to T cells, and certain HLA types may be more likely to present drug-related antigens in a way that triggers an aberrant immune response targeting the liver. journals.co.zaresearchgate.net

Further research is needed to fully elucidate the complex interplay between genetic factors, including specific HLA alleles, and other contributing factors in determining an individual's risk of developing this compound-induced liver injury.

Research Findings on HLA-A*33:01 and DILI (Selected Data)

Note: The data presented in this table are based on findings from specific studies and may not be exhaustive or universally applicable. Allele frequencies can vary among different populations.