Cells. 2023 Apr 12;12(8):1141. doi: 10.3390/cells12081141.

ABSTRACT

The poor prognosis of most cases of advanced cholangiocarcinoma (CCA) constitutes a severe problem in modern oncology, which is aggravated by the fact that the incidence of this liver cancer is increasing worldwide and is often diagnosed late, when surgical removal is not feasible. The difficulty of dealing with this deadly tumor is augmented by the heterogeneity of CCA subtypes and the complexity of mechanisms involved in enhanced proliferation, apoptosis avoidance, chemoresistance, invasiveness, and metastasis that characterize CCA. Among the regulatory processes implicated in developing these malignant traits, the Wnt/β-catenin pathway plays a pivotal role. Alteration of β-catenin expression and subcellular localization has been associated with worse outcomes in some CCA subtypes. This heterogeneity, which also affects cellular and in vivo models commonly used to study CCA biology and anticancer drug development, must be taken into account for CCA investigation to more accurately extrapolate basic laboratory research to the clinical situation. A better understanding of the altered Wnt/β-catenin pathway in relationship with the heterogeneous forms of CCA is mandatory for developing novel diagnostic tools and therapeutic strategies for patients suffering from this lethal disease.

PMID:37190050 | DOI:10.3390/cells12081141

Biomedicines. 2023 Apr 5;11(4):1098. doi: 10.3390/biomedicines11041098.

ABSTRACT

Acute myeloid leukemia (AML) is a hematologic malignancy that occurs due to alterations such as genetic mutations, chromosomal translocations, or changes in molecular levels. These alterations can accumulate in stem cells and hematopoietic progenitors, leading to the development of AML, which has a prevalence of 80% of acute leukemias in the adult population. Recurrent cytogenetic abnormalities, in addition to mediating leukemogenesis onset, participate in its evolution and can be used as established diagnostic and prognostic markers. Most of these mutations confer resistance to the traditionally used treatments and, therefore, the aberrant protein products are also considered therapeutic targets. The surface antigens of a cell are characterized through immunophenotyping, which has the ability to identify and differentiate the degrees of maturation and the lineage of the target cell, whether benign or malignant. With this, we seek to establish a relationship according to the molecular aberrations and immunophenotypic alterations that cells with AML present.

PMID:37189716 | DOI:10.3390/biomedicines11041098

Pharmgenomics Pers Med. 2023 May 8;16:433-441. doi: 10.2147/PGPM.S403655. eCollection 2023.

ABSTRACT

BACKGROUND AND AIMS: It is crucial to provide healthcare personnel with the necessary knowledge and understanding of genetic testing and pharmacogenomics. The purpose of this study is to assess the knowledge, attitudes, views, and considerations of Community pharmacists (CPs) about pharmacogenomics and genetics.

METHODS AND MATERIALS: A cross-sectional web-based study was conducted among practicing pharmacists Between January and February of 2022. Participants were recruited through a convenient sampling technique. A total of 23 item questionnaires were used to assess the Knowledge Attitudes, Views, and Considerations toward Pharmacogenomics among pharmacists.

RESULTS: The mean age of the CPs were 28.45±7.29(Std). Among the CPs, 38.4% (98 of 255) of them were correctly identified human chromosomes, and the majority of them 73.3% knew that adverse reactions can be caused by genetic changes in the human body. A total of 194 CPs agreed that certain drugs can be affected by genetic changes in the patient. In this study, one-third (33%) of the CPs were found to have good knowledge, while most (66.3%) of the CPs were found poor knowledge of pharmacogenomics and genetics. Furthermore, the knowledge score is significantly different concerning the qualification of the CPs (p=0.0001).

CONCLUSION: The current findings, demonstrated a majority of the CPs found a lack of knowledge and understanding regarding pharmacogenomics and its perspectives, there is a need to increase awareness among CPs to reduce the knowledge gap of pharmacogenomics and genetics.

PMID:37187880 | PMC:PMC10179052 | DOI:10.2147/PGPM.S403655

J Transl Med. 2023 May 15;21(1):324. doi: 10.1186/s12967-023-04086-7.

ABSTRACT

BACKGROUND: In Lung adenocarcinoma (LUAD), targeted therapies and immunotherapies have moved from metastatic to early stage and stratification of the relapse risk becomes mandatory. Here we identified a miR-200 based RNA signature that delineates Epithelial-to-mesenchymal transition (EMT) heterogeneity and predicts survival beyond current classification systems.

METHODS: A miR-200 signature was identified using RNA sequencing. We scored the miR-200 signature by WISP (Weighted In Silico Pathology), used GSEA to identify pathway enrichments and MCP-counter to characterize immune cell infiltrates. We evaluate the clinical value of this signature in our series of LUAD and using TCGA and 7 published datasets.

RESULTS: We identified 3 clusters based on supervised classification: I is miR-200-sign-down and enriched in TP53 mutations IIA and IIB are miR-200-sign-up: IIA is enriched in EGFR (p < 0.001), IIB is enriched in KRAS mutation (p < 0.001). WISP stratified patients into miR-200-sign-down (n = 65) and miR-200-sign-up (n = 42). Several biological processes were enriched in MiR-200-sign-down tumors, focal adhesion, actin cytoskeleton, cytokine/receptor interaction, TP53 signaling and cell cycle pathways. Fibroblast, immune cell infiltration and PDL1 expression were also significantly higher suggesting immune exhaustion. This signature stratified patients into high-vs low-risk groups, miR-200-sign-up had higher DFS, median not reached at 60 vs 41 months and within subpopulations with stage I, IA, IB, or II. Results were validated on TCGA data on 7 public datasets.

CONCLUSION: This EMT and miR-200-related prognostic signature refines prognosis evaluation independently of tumor stage and paves the way towards assessing the predictive value of this LUAD clustering to optimize perioperative treatment.

PMID:37189151 | DOI:10.1186/s12967-023-04086-7

Curr Issues Mol Biol. 2023 Apr 17;45(4):3479-3514. doi: 10.3390/cimb45040228.

ABSTRACT

Cannabis and related compounds have created significant research interest as a promising therapy in many disorders. However, the individual therapeutic effects of cannabinoids and the incidence of side effects are still difficult to determine. Pharmacogenomics may provide the answers to many questions and concerns regarding the cannabis/cannabinoid treatment and help us to understand the variability in individual responses and associated risks. Pharmacogenomics research has made meaningful progress in identifying genetic variations that play a critical role in interpatient variability in response to cannabis. This review classifies the current knowledge of pharmacogenomics associated with medical marijuana and related compounds and can assist in improving the outcomes of cannabinoid therapy and to minimize the adverse effects of cannabis use. Specific examples of pharmacogenomics informing pharmacotherapy as a path to personalized medicine are discussed.

PMID:37185752 | DOI:10.3390/cimb45040228

Front Pediatr. 2023 Apr 26;11:1155449. doi: 10.3389/fped.2023.1155449. eCollection 2023.

ABSTRACT

Overall survival after cancer is increasing for the majority of cancer types, but survivors can be burdened lifelong by treatment-related severe toxicities. Integration of long-term toxicities in treatment evaluation is not least important for children and young adults with cancers with high survival probability. We present modified consensus definitions of 21 previously published physician-defined Severe Toxicities (STs), each reflecting the most serious long-term treatment-related toxicities and representing an unacceptable price for cure. Applying the Severe Toxicity (ST) concept to real-world data required careful adjustments of the original consensus definitions, translating them into standardized endpoints for evaluating treatment-related outcomes to ensure that (1) the STs can be classified uniformly and prospectively across different cohorts, and (2) the ST definitions allow for valid statistical analyses. The current paper presents the resulting modified consensus definitions of the 21 STs proposed to be included in outcome reporting of cancer treatment.

PMID:37181427 | PMC:PMC10171426 | DOI:10.3389/fped.2023.1155449

J Hum Kinet. 2023 Jan 20;86:155-164. doi: 10.5114/jhk/159463. eCollection 2023 Mar.

ABSTRACT

Endurance performance is positively associated with hematological adaptations; therefore, high total hemoglobin mass and intravascular volumes are commonly observed in high-level endurance athletes. However, it is still unclear whether the fluctuations in exercise capacity that typically occur in endurance athletes during the annual training cycle are directly associated with changes in hematological adaptations, which appear to be relatively stable during this time. To better understand this issue, a study was conducted with 10 Olympic rowers, who followed the same training program. Athletes underwent laboratory testing in the competitive and the general preparation phase of an annual training cycle (a 34% reduction in training volume). This included a graded exercise test on a rowing ergometer (GXT) and blood measurements of hemoglobin concentration (Hb), total hemoglobin mass (tHb-mass), plasma volume (PV), and blood volume (BV). Decreases in maximal values of power relative to body mass (p = 0.028), lactate concentration (p = 0.005), and heart rate (p = 0.017) in the GXT were registered. At the same time, absolute (p = 0.017) and relative (p = 0.005) PV decreased. Changes in PV (rS = 0.842, p = 0.002) and BV (rS = 0.818, p = 0.004), but not in tHb-mass (rS = 0.588, p = 0.074) and Hb (rS = -0.188, p = 0.602), were significantly correlated with changes in maximal power in the GXT. Our results indicate a close relationship between changes in intravascular volumes and maximal exercise capacity after a period of reduced training loads in elite endurance athletes.

PMID:37181268 | PMC:PMC10170542 | DOI:10.5114/jhk/159463

Front Pharmacol. 2023 Apr 26;14:1183491. doi: 10.3389/fphar.2023.1183491. eCollection 2023.

ABSTRACT

Drug-induced delayed hypersensitivity reactions (DHRs) is still a clinical and healthcare burden in every country. Increasing reports of DHRs have caught our attention to explore the genetic relationship, especially life-threatening severe cutaneous adverse drug reactions (SCARs), including acute generalized exanthematous pustulosis (AGEP), drug reactions with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). In recent years, many studies have investigated the immune mechanism and genetic markers of DHRs. Besides, several studies have stated the associations between antibiotics-as well as anti-osteoporotic drugs (AOD)-induced SCARs and specific human leukocyte antigens (HLA) alleles. Strong associations between drugs and HLA alleles such as co-trimoxazole-induced DRESS and HLA-B*13:01 (Odds ratio (OR) = 45), dapsone-DRESS and HLA-B*13:01 (OR = 122.1), vancomycin-DRESS and HLA-A*32:01 (OR = 403), clindamycin-DHRs and HLA-B*15:27 (OR = 55.6), and strontium ranelate (SR)-SJS/TEN and HLA-A*33:03 (OR = 25.97) are listed. We summarized the immune mechanism of SCARs, update the latest knowledge of pharmacogenomics of antibiotics- and AOD-induced SCARs, and indicate the potential clinical use of these genetic markers for SCARs prevention in this mini review article.

PMID:37180708 | PMC:PMC10169607 | DOI:10.3389/fphar.2023.1183491

Indian Heart J. 2023 May 11:S0019-4832(23)00074-3. doi: 10.1016/j.ihj.2023.05.002. Online ahead of print.

ABSTRACT

During the COVID-19 pandemic, the pharmaco-invasive approach in the management of ST Elevation Myocardial Infarction (STEMI) played a vital role in saving many lives. A retrospective observational study was conducted wherein 134 patients presenting with STEMI between (Dec 2019 - Mar 2022) were thrombolysed with either streptokinase or tenecteplase in a centre where primary PCI was not available. There was no significant difference in the outcomes and their predictors between the SK and TNK groups. A prospective study with a larger sample size in the Indian population will be able to provide more substantial and promising results for further interventions.

PMID:37178868 | DOI:10.1016/j.ihj.2023.05.002

Plants (Basel). 2023 Apr 25;12(9):1756. doi: 10.3390/plants12091756.

ABSTRACT

The pharmacological properties of plants lie in the content of secondary metabolites that are classified into different categories based on their biosynthesis, structures, and functions. MicroRNAs (miRNAs) are small non-coding RNA molecules that play crucial post-transcriptional regulatory roles in plants, including development and stress-response signaling; however, information about their involvement in secondary metabolism is still limited. Cumin is one of the most popular seeds from the plant Cuminum cyminum, with extensive applications in herbal medicine and cooking; nevertheless, no previous studies focus on the miRNA profile of cumin. In this study, the miRNA profile of C. cyminum and its association with the biosynthesis of secondary metabolites were determined using NGS technology. The sequencing data yielded 10,956,054 distinct reads with lengths ranging from 16 to 40 nt, of which 349 miRNAs were found to be conserved and 39 to be novel miRNAs. Moreover, this work identified 1959 potential target genes for C. cyminum miRNAs. It is interesting to note that several conserved and novel miRNAs have been found to specifically target important terpenoid backbone, flavonoid biosynthesis, and lipid/fatty acid pathways enzymes. We believe this investigation will aid in elucidating the implications of miRNAs in plant secondary metabolism.

PMID:37176813 | DOI:10.3390/plants12091756

Int J Mol Sci. 2023 Apr 24;24(9):7763. doi: 10.3390/ijms24097763.

ABSTRACT

Newborns and especially preterm infants are much more susceptible to infections than adults. Due to immature adaptive immunity, especially innate immune cells play an important role in a newborn's infection defense. Neonatal neutrophils exhibit profound differences in their functionality compared to neutrophils of adults. In particular, neonates possess a relevant population of suppressive neutrophils, which not only inhibit but also specifically modulate the function of T-cells. In this study, we investigated whether neonatal neutrophils are already involved in T-cell development in the thymus. For this purpose, we used a newly developed model of antibody-mediated immune cell depletion in which we administered a depleting antibody to pregnant and then lactating dams. Using this method, we were able to sufficiently deplete Ly6G-positive neutrophils in offspring. We demonstrated that the depletion of neutrophils in newborn mice resulted in altered peripheral T-cell homeostasis with a decreased CD4+/CD8+ T-cell ratio and decreased expression of CD62L. Neutrophil depletion even affected T-cell development in the thymus, with increased double positive thymocytes and a decreased CD4+/CD8+ single positive thymocyte ratio. Altogether, we demonstrated a previously unknown mechanism mediating neutrophils' immunomodulatory effects in newborns.

PMID:37175470 | DOI:10.3390/ijms24097763

Molecules. 2023 Apr 25;28(9):3698. doi: 10.3390/molecules28093698.

ABSTRACT

Cancer treatments with targeted therapy have gained immense interest due to their low levels of toxicity and high selectivity. Proteolysis-Targeting Chimeras (PROTACs) have drawn special attention in the development of cancer therapeutics owing to their unique mechanism of action, their ability to target undruggable proteins, and their focused target engagement. PROTACs selectively degrade the target protein through the ubiquitin-proteasome system, which describes a different mode of action compared to conventional small-molecule inhibitors or even antibodies. Among different cancer types, prostate cancer (PC) is the most prevalent non-cutaneous cancer in men. Genetic alterations and the overexpression of several genes, such as FOXA1, AR, PTEN, RB1, TP53, etc., suppress the immune response, resulting in drug resistance to conventional drugs in prostate cancer. Since the progression of ARV-110 (PROTAC for PC) into clinical phases, the focus of research has quickly shifted to protein degraders targeting prostate cancer. The present review highlights an overview of PROTACs in prostate cancer and their superiority over conventional inhibitors. We also delve into the underlying pathophysiology of the disease and explain the structural design and linkerology strategies for PROTAC molecules. Additionally, we touch on the various targets for PROTAC in prostate cancer, including the androgen receptor (AR) and other critical oncoproteins, and discuss the future prospects and challenges in this field.

PMID:37175108 | DOI:10.3390/molecules28093698

BMC Psychiatry. 2023 May 12;23(1):334. doi: 10.1186/s12888-023-04756-2.

ABSTRACT

BACKGROUND: Pharmacogenomic testing guided treatment have been developed to guide drug selection or conversion in major depressive disorder patients. Whether patients benefit from pharmacogenetic testing remains unclear. We aim to evaluates the effect of pharmacogenomic testing guiding on clinical outcomes of major depressive disorder.

METHODS: Pubmed, Embase, and Cochrane Library of Clinical Trials were searched from inception until August 2022. Key terms included pharmacogenomic and antidepressive. Odds ratios (RR) with 95% confidence intervals (95%CIs) were calculated using fixed-effects model for low or moderate heterogeneity or random-effects model for high heterogeneity.

RESULTS: Eleven studies (5347 patients) were included. Compared with usual group, pharmacogenomic testing guided group was associated with an increased response rate at week 8 (OR 1.32, 95%CI 1.15-1.53, 8 studies, 4328 participants) and week 12 (OR 1.36, 95%CI 1.15-1.62, 4 studies, 2814 participants). Similarly, guided group was associated with an increased rate of remission at week 8 (OR 1.58, 95%CI 1.31-1.92, 8 studies, 3971 participants) and week 12 (OR 2.23, 95%CI 1.23-4.04, 5 studies, 2664 participants). However, no significant differences were found between the two groups in response rate at week 4 (OR 1.12, 95%CI 0.89-1.41, 2 studies, 2261 participants) and week 24 (OR 1.16, 95%CI 0.96-1.41, 2 studies, 2252 participants), and remission rate at week 4 (OR 1.26, 95%CI 0.93-1.72, 2 studies, 2261 participants) and week 24 (OR 1.06, 95%CI 0.83-1.34, 2 studies, 2252 participants). Medication congruence in 30 days was significantly reduced in the pharmacogenomic guided group compared with the usual care group (OR 2.07, 95%CI 1.69-2.54, 3 studies, 2862 participants). We found significant differences between subgroups of target population in response and remission rate.

CONCLUSION: Patients with major depressive disorder may benefit from pharmacogenomic testing guided treatment by achieving target response and remission rates more quickly.

PMID:37173736 | DOI:10.1186/s12888-023-04756-2

Mol Psychiatry. 2023 May 12. doi: 10.1038/s41380-023-02082-3. Online ahead of print.

ABSTRACT

Patients suffering from mental disorders are at high risk of developing cardiovascular diseases, leading to a reduction in life expectancy. Genetic variants can display greater influence on cardiometabolic features in psychiatric cohorts compared to the general population. The difference is possibly due to an intricate interaction between the mental disorder or the medications used to treat it and metabolic regulations. Previous genome wide association studies (GWAS) on antipsychotic-induced weight gain included a low number of participants and/or were restricted to patients taking one specific antipsychotic. We conducted a GWAS of the evolution of body mass index (BMI) during early (i.e., ≤ 6) months of treatment with psychotropic medications inducing metabolic disturbances (i.e., antipsychotics, mood stabilizers and some antidepressants) in 1135 patients from the PsyMetab cohort. Six highly correlated BMI phenotypes (i.e., BMI change and BMI slope after distinct durations of psychotropic treatment) were considered in the analyses. Our results showed that four novel loci were associated with altered BMI upon treatment at genome-wide significance (p < 5 × 10-8): rs7736552 (near MAN2A1), rs11074029 (in SLCO3A1), rs117496040 (near DEFB1) and rs7647863 (in IQSEC1). Associations between the four loci and alternative BMI-change phenotypes showed consistent effects. Replication analyses in 1622 UK Biobank participants under psychotropic treatment showed a consistent association between rs7736552 and BMI slope (p = 0.017). These findings provide new insights into metabolic side effects induced by psychotropic drugs and underline the need for future studies to replicate these associations in larger cohorts.

PMID:37173452 | DOI:10.1038/s41380-023-02082-3

J Psychiatry Neurosci. 2023 May 12;48(3):E153. doi: 10.1503/jpn.230048-l. Print 2023 May-Jun.

NO ABSTRACT

PMID:37172963 | DOI:10.1503/jpn.230048-l

J Psychiatry Neurosci. 2023 May 12;48(3):E151-E152. doi: 10.1503/jpn.230022-l. Print 2023 May-Jun.

NO ABSTRACT

PMID:37172962 | DOI:10.1503/jpn.230022-l

Psychiatry Res. 2023 May 6;325:115246. doi: 10.1016/j.psychres.2023.115246. Online ahead of print.

ABSTRACT

The purpose of this study was to report current practices and attitudes of child and adolescent psychiatrists (CAP) regarding diagnostic genetic and pharmacogenetic (PGx) testing. We surveyed 958 US-based practicing CAP. 54.9% of respondents indicated that they had ordered/referred for a genetic test in the past 12 months. 87% of respondents agreed that it is their role to discuss genetic information regarding psychiatric conditions with their patients; however, 45% rated their knowledge of genetic testing practice guidelines as poor/very poor. The most ordered test was PGx (32.2%), followed by chromosomal microarray (23.0%). 73.4% reported that PGx is at least slightly useful in child and adolescent psychiatry. Most (62.8%) were asked by a patient/family to order PGx in the past 12 months and 41.7% reported they would order PGx in response to a family request. Those who ordered a PGx test were more likely to have been asked by a patient/family and to work in private practice. 13.8% of respondents agreed/strongly agreed that a PGx test can predict the effectiveness of specific antidepressants. Some respondents also indicated they would make clinical changes based on PGx information even if a medication was currently effective and there were no side effects. Genetic testing has become routine clinical care in child and adolescent psychiatry. Despite this, many providers rate their associated knowledge as poor/very poor. Patient requests were associated with ordering practices and providers misinterpretation of PGx may be leading to unnecessary changes in clinical management. There is need for further education and support for clinicians.

PMID:37172398 | DOI:10.1016/j.psychres.2023.115246

Front Psychiatry. 2023 Apr 24;14:1169787. doi: 10.3389/fpsyt.2023.1169787. eCollection 2023.

ABSTRACT

Psychosis spectrum disorders (PSDs), as well as other severe mental illnesses where psychotic features may be present, like bipolar disorder, are associated with intrinsic metabolic abnormalities. Antipsychotics (APs), the cornerstone of treatment for PSDs, incur additional metabolic adversities including weight gain. Currently, major gaps exist in understanding psychosis illness biomarkers, as well as risk factors and mechanisms for AP-induced weight gain. Metabolomic profiles may identify biomarkers and provide insight into the mechanistic underpinnings of PSDs and antipsychotic-induced weight gain. In this 12-week prospective naturalistic study, we compared serum metabolomic profiles of 25 cases within approximately 1 week of starting an AP to 6 healthy controls at baseline to examine biomarkers of intrinsic metabolic dysfunction in PSDs. In 17 of the case participants with baseline and week 12 samples, we then examined changes in metabolomic profiles over 12 weeks of AP treatment to identify metabolites that may associate with AP-induced weight gain. In the cohort with pre-post data (n = 17), we also compared baseline metabolomes of participants who gained ≥5% baseline body weight to those who gained <5% to identify potential biomarkers of antipsychotic-induced weight gain. Minimally AP-exposed cases were distinguished from controls by six fatty acids when compared at baseline, namely reduced levels of palmitoleic acid, lauric acid, and heneicosylic acid, as well as elevated levels of behenic acid, arachidonic acid, and myristoleic acid (FDR < 0.05). Baseline levels of the fatty acid adrenic acid was increased in 11 individuals who experienced a clinically significant body weight gain (≥5%) following 12 weeks of AP exposure as compared to those who did not (FDR = 0.0408). Fatty acids may represent illness biomarkers of PSDs and early predictors of AP-induced weight gain. The findings may hold important clinical implications for early identification of individuals who could benefit from prevention strategies to reduce future cardiometabolic risk, and may lead to novel, targeted treatments to counteract metabolic dysfunction in PSDs.

PMID:37168086 | PMC:PMC10164938 | DOI:10.3389/fpsyt.2023.1169787

Nat Genet. 2023 May 11. doi: 10.1038/s41588-023-01390-2. Online ahead of print.

ABSTRACT

Mobile genetic elements (MEs) are heritable mutagens that recursively generate structural variants (SVs). ME variants (MEVs) are difficult to genotype and integrate in statistical genetics, obscuring their impact on genome diversification and traits. We developed a tool that accurately genotypes MEVs using short-read whole-genome sequencing (WGS) and applied it to global human populations. We find unexpected population-specific MEV differences, including an Alu insertion distribution distinguishing Japanese from other populations. Integrating MEVs with expression quantitative trait loci (eQTL) maps shows that MEV classes regulate tissue-specific gene expression by shared mechanisms, including creating or attenuating enhancers and recruiting post-transcriptional regulators, supporting class-wide interpretability. MEVs more often associate with gene expression changes than SNVs, thus plausibly impacting traits. Performing genome-wide association study (GWAS) with MEVs pinpoints potential causes of disease risk, including a LINE-1 insertion associated with keloid and fasciitis. This work implicates MEVs as drivers of human divergence and disease risk.

PMID:37169872 | DOI:10.1038/s41588-023-01390-2

Int J Clin Pharm. 2023 May 11. doi: 10.1007/s11096-023-01588-8. Online ahead of print.

ABSTRACT

BACKGROUND: Pharmacogenetics (PGx), especially in regard to CYP2D6, is gaining more importance in routine clinical settings. Including phenoconversion effects (PC) in result interpretation could maximize its potential benefits. However, studies on genetics of pharmacokinetic genes including the functional enzyme status are lacking.

AIM: The retrospective analyses of clinical routine data aimed to investigating how the CYP2D6 functional enzyme status affects serum concentrations and metabolite-to-parent ratios of seven common psychotropic drugs and allows an evaluation of the relevance of this information for patient care.

METHOD: Two patient cohorts (total n = 316; 44.2 ± 15.4 years) were investigated for the CYP2D6 functional enzyme status and its associations with drug exposure and metabolism of venlafaxine, amitriptyline, mirtazapine, sertraline, escitalopram, risperidone and quetiapine.

RESULTS: We found an increase in intermediate and poor metabolizers, as well as a decrease in normal metabolizers of CYP2D6 when including PC. Moreover, we found associations between amitriptyline exposure with the phenoconversion-corrected activity score of CYP2D6 (Spearman correlation; p = 0.03), and risperidone exposure with CYP2D6 functional enzyme status (Kruskal-Wallis test; p = 0.01), as well as between metabolite-to-parent ratio of venlafaxine and risperidone with CYP2D6 functional enzyme status (Kruskal-Wallis test; p < 0.001; p = 0.05).

CONCLUSION: The data stress the relevance of PC-informed PGx in psychopharmacological treatment and suggest that PC should be included in PGx result interpretation when PGx is implemented in routine clinical care, especially before initiating amitriptyline- or risperidone-treatment, to start with a dose adequate to the respective CYP2D6 functional enzyme status. Moreover, PGx and therapeutic drug monitoring should be used complementary but not alternatively.

PMID:37166747 | DOI:10.1007/s11096-023-01588-8