BMC Infect Dis. 2025 Feb 1;25(1):153. doi: 10.1186/s12879-025-10538-w.

ABSTRACT

BACKGROUND: Anti-infective medicines are crucial for treating infections, but improper dosing can cause toxicity, resistance and treatment failure. Pharmacogenomics can address genetic variations affecting drug efficacy and safety. Despite the high burden of diseases like TB and HIV in Sri Lanka and South Asia, pharmacogenomic data for these populations are limited. This study aims to fill this gap by investigating pharmacogenomic variants in a South Asian population from Sri Lankan.

METHODS: Pharmacogenomic data on anti-infective medicines were obtained from the PharmGKB database, selecting variants with evidence levels 1 A, 1B, 2 A, and 2B. Sri Lankan genetic data were sourced from an anonymized database of 670 Sri Lankans maintained by the Centre for Genetics and Genomics, Faculty of Medicine, University of Colombo. MAFs were compared between Sri Lankan sub-populations and global data from gnomAD, with statistical significance set at p < 0.05.

RESULTS: MAFs of NAT2 gene rs1041983 and rs1799931 variants were, 43.7% (95%CI:41.1-46.4), 7.3% (95%CI:6.0-8.8), respectively. The UGT1A1 rs4148323 variant had a MAF of 3.5% (95%CI:2.6-4.6). In the CYP2B6 gene, 109 individuals were homozygous for the rs3745274 (poor metaboliser) variant, with a MAF of 39.6% (95%CI:37.0-42.3), while the rs34097093 and rs28399499 variants had no individuals homozygous for the variant (MAF: 0.2% [95%CI:0-0.5] (poor/intermediate metaboliser), and 0.1% [95%CI:0-0.4] (poor/intermediate metaboliser), respectively). The MAFs of the CYP2C19 rs12769205 (poor/intermediate metaboliser), rs4244285 (poor/intermediate metaboliser), rs3758581 (poor/intermediate metaboliser), and rs4986893 (poor/intermediate metaboliser) variants were 41.9% (95%CI:39.3-44.6), 41.9% (95%CI:39.2-44.7), 9.7% (95%CI:8.2-11.4), and 0.5% [(95%CI:0.2-1.1), respectively. Most variants showed significant differences compared to global populations, with some exhibiting higher frequencies, particularly when compared to Europeans. CYP2C19 rs12769205 and rs4244285 exhibited higher MAFs in Sri Lankans compared to both other South Asians and Europeans. The NAT2 rs1041983, NAT2 rs1799931, CYP2C19 rs4986893, CYP2C19 rs3758581, and CYP2B6 rs3745274 variants demonstrated significantly higher MAFs than in Europeans but not significantly different from South Asians.

CONCLUSION: This preliminary study identifies variants in NAT2, UGT1A1, CYP2B6, and CYP2C19 genes relevant to the metabolism of anti-TB drugs, antiretrovirals, and voriconazole among Sri Lankans. Several variants, including CYP2C19 rs12769205 and rs4244285, showed higher MAFs, particularly in comparison to European populations, indicating potential differences in drug response. However, the nature of the study limits the ability to explore clinical correlations with the genotypes, therefore further research focusing on clinical correlation and functional validation is required.

PMID:39893405 | DOI:10.1186/s12879-025-10538-w

Cytokine. 2025 Jan 31;187:156870. doi: 10.1016/j.cyto.2025.156870. Online ahead of print.

ABSTRACT

OBJECTIVE: Preeclampsia, characterized by hypertension and proteinuria, is a medical condition associated with maternal and fetal morbidity and mortality. Previous studies reported conflicting correlations between the eNOS rs2070744 variant and the occurrence of preeclampsia. Due to inconsistencies in findings, the purpose of the present meta-analysis was to explore the precise link between the eNOS rs2070744 variant and the development of preeclampsia.

METHODS: The articles were retrieved from various online sources, including Cochrane Library, Google Scholar, EMBASE, PubMed, and Web of Science databases up to February 2024. Data were analyzed by Review Manager (RevMan) 5.4. We adhered to the PRISMA 2020 guidelines to conduct this meta-analysis.

RESULTS: A total of 26 articles containing 3741 cases and 4920 controls were included for qualitative and quantitative data synthesis. In the overall population, we found a strong correlation between the eNOS rs2070744 variant and higher preeclampsia risk in recessive (CC vs. CT + TT: OR = 1.31, p = 0.017) dominant (CC + CT vs. TT: OR = 1.14, p = 0.051), co-dominant 2 (CC vs. TT: OR = 1.37, p = 0.011) and allelic (C vs. T: OR = 1.14, p = 0.022) models. Our study also explored similar outcomes among the Caucasian population in dominant (CC + CT vs. TT: OR = 1.16, p = 0.048), recessive (CC vs. CT + TT: OR = 1.46, p = 0.027), allele (C vs. T: OR = 1.18, p = 0.044), co-dominant 2 (CC vs. TT: OR = 1.53, p = 0.027), and co-dominant 3 (CC vs. CT: OR = 1.46, p = 0.002) models. Besides, a significant risk of preeclampsia in the African population was observed in co-dominant 2 (CC vs. TT: OR = 2.11, p = 0.009), dominant (CC + CT vs. TT: OR = 1.58, p = 0.002) and allelic (C vs. T: OR = 1.45, p = 0.001) models. However, no association of this polymorphism with preeclampsia risk was reported in Asian and mixed populations.

CONCLUSION: This study suggests a significant correlation between eNOS rs2070744 polymorphism and preeclampsia. However, more research on various ethnic groups is necessary to confirm the association.

PMID:39892025 | DOI:10.1016/j.cyto.2025.156870

Clin Transl Sci. 2025 Feb;18(2):e70136. doi: 10.1111/cts.70136.

ABSTRACT

High-dose methotrexate (HD-MTX) infusions are commonly used to consolidate remission in children with acute lymphoblastic leukemia (ALL). We investigate the potential role of candidate polymorphisms in SLCO1B1 (rs4149056 and rs2306283), ABCB1 (rs1045642), ABCC2 (rs717620), ABCC3 (rs9895420), and ABCC4 (rs7317112) drug transporters genes on HD-MTX pharmacokinetics and patients' outcome (meant both as relapse and drug-related toxicities) in an Italian cohort of 204 ALL pediatric patients treated according to the AIEOP-BFM ALL 2009 protocol. TaqMan SNP genotyping assays determined patient's genotypes. Measurements of HD-MTX plasma concentration were available for 814 HD-MTX courses in 204 patients; MTX clearance was estimated by a two-compartmental linear pharmacokinetic model with first-order elimination and a Bayesian approach, via ADAPT. Independent contributions of age and ABCC4 SNP rs7317112 (A>G, intronic) on MTX clearance were detected in a multivariate analysis (p = 1.57 × 10-8 and p = 2.06 × 10-5, respectively), suggesting a delayed elimination of the drug in older patients and an accelerated one in carriers of the variant GG genotype. After multiple corrections, the association between ABCC2 SNP rs717620 (-24 C>T) and severe hematological toxicity was found (p < 0.005). Moreover, SLCO1B1 SNP rs4149056 (c.521T>C, p.V174A) affected patients' outcomes: carriers of the variant C allele presented a reduced risk of relapse compared to wild-type TT (hazard risk: 0.27, 95% confidence interval [CI]: 0.08-0.90, p = 0.037). Taken together, these data highlighted the importance of variants in drug transporters genes on HD-MTX disposition in the AIEOP-BFM ALL 2009 protocol consolidation phase, and their putative role as predictive markers of outcome.

PMID:39891427 | DOI:10.1111/cts.70136

Clin Pharmacol Ther. 2025 Jan 31. doi: 10.1002/cpt.3572. Online ahead of print.

ABSTRACT

Ritonavir-boosted atazanavir is a victim of drug-drug interaction with rifampicin, a key component of antitubercular treatment. In a recent dose escalation clinical trial, we showed that increasing atazanavir/ritonavir to 300/100 mg b.i.d. compensates for reduced drug exposure in plasma due to rifampicin, but the intracellular effects remained unexplored. This sub-study investigated the intracellular penetration of atazanavir/ritonavir and dolutegravir into peripheral blood mononuclear cells (PBMC). Twenty-six healthy volunteers living with HIV, virologically suppressed, and taking atazanavir/ritonavir containing regimens were enrolled. The trial consisted of four sequential periods: PK1, participants were on atazanavir/ritonavir 300/100 mg q.d.; at PK2, rifampicin 600 mg q.d. and dolutegravir 50 mg b.i.d. were added (2 weeks); at PK3, atazanavir/ritonavir dose was increased to 300/100 mg b.i.d. (1 week); at PK4, rifampicin dose was doubled (1 week). Atazanavir, ritonavir, and dolutegravir were quantified in plasma and PBMC using LC-MS/MS methods to evaluate steady-state concentrations at the end of each period. Atazanavir/ritonavir dose escalation successfully restored intracellular concentrations comparable to those observed without rifampicin, with a geometric mean ratio of 0.99 (CI90 0.72-1.41) for atazanavir at PK3 compared with PK1. The intracellular concentration of dolutegravir increased significantly with atazanavir/ritonavir dose escalation, similar to plasma. Finally, further, increasing the rifampicin dose did not show an additional impact on atazanavir/ritonavir concentrations in PBMC. The study confirms that increasing the ATV/r dose can be an effective strategy for compensating rifampicin effects even at the intracellular level, supporting its use in clinical settings.

PMID:39891354 | DOI:10.1002/cpt.3572

Anesthesiol Clin. 2025 Mar;43(1):127-140. doi: 10.1016/j.anclin.2024.08.001. Epub 2024 Sep 17.

ABSTRACT

Biological sex as a variable in pain perception has been rigorously studied. However, there is little correlation between clinical and experimental studies with regard to this. There has been a surge of interest and research in the correlation of genes and single-nucleotide polymorphisms in relation to pain perception, and opioid pharmacokinetics. However, there have not yet been studies or reports of generalized application of this testing to improve acute postoperative pain outcomes.

PMID:39890315 | DOI:10.1016/j.anclin.2024.08.001

Reprod Biomed Online. 2024 Oct 21;50(3):104494. doi: 10.1016/j.rbmo.2024.104494. Online ahead of print.

ABSTRACT

Persistent Müllerian duct syndrome (PMDS) is a rare autosomal recessive syndrome characterized by the coexistence of Müllerian derivatives in a normally virilized male, caused by mutations in the AMH or AMHR2 gene. This paper reports the case of a 33-year-old man with PMDS, diagnosed late during an infertility check-up. Exploratory laparoscopy revealed two intra-pelvic gonads and Müllerian duct structures. Genetic analysis identified an undescribed homozygous missense mutation in the fifth exon of AMH. Typically, PMDS is diagnosed in the presence of cryptorchidism or inguinal hernia, and rarely in the context of infertility. Early orchidopexy is recommended to mitigate fertility sequelae while preserving endogenous hormone secretion. This late diagnosis of PMDS led to a discussion of the management of infertility, surgical strategies and adult follow-up. In this case, the decision was made with the patient to perform minimally invasive surgery, specifically unilateral orchidectomy for fertility management. The biopsy revealed no spermatozoa, probably due to prolonged untreated pelvic cryptorchidism. Retaining one testicle maintains endogenous testosterone production, thus avoiding imperfect hormonal replacement. Given the risk of tumoural degeneration, albeit a low one, annual imaging follow-up is mandatory and removal of Müllerian structures and gonadectomy may be considered if necessary.

PMID:39889328 | DOI:10.1016/j.rbmo.2024.104494

Clin Pharmacol Ther. 2025 Jan 31. doi: 10.1002/cpt.3567. Online ahead of print.

ABSTRACT

The safety of systemic fluoropyrimidines (e.g., 5-fluorouracil, capecitabine) is impacted by germline genetic variants in DPYD, which encodes the dihydropyrimidine dehydrogenase (DPD) enzyme that functions as the rate-limiting step in the catabolism of this drug class. Genetic testing to identify those with DPD deficiency can help mitigate the risk of severe and life-threatening fluoropyrimidine-induced toxicities. Globally, the integration of DPYD genetic testing into patient care has varied greatly, ranging from being required as the standard of care in some countries to limited clinical use in others. Thus, implementation strategies have evolved differently across health systems and countries. The primary objective of this tutorial is to provide practical considerations and best practice recommendations for the implementation of DPYD-guided systemic fluoropyrimidine dosing. We adapted the Exploration, Preparation, Implementation, and Sustainment (EPIS) framework to cover topics including the clinical evidence supporting DPYD genotyping to guide fluoropyrimidine therapy, regulatory guidance for DPYD genotyping, key stakeholder engagement, logistics for DPYD genotyping, development of point-of-care clinical decision support tools, and considerations for the creation of sustainable and scalable DPYD genotype-integrated workflows. This guide also describes approaches to counseling patients about DPYD testing and result disclosure, along with examples of patient and provider educational resources. Together, DPYD testing and clinical practice integration aim to promote safe prescribing of fluoropyrimidine therapy and decrease the risk of severe and life-threatening fluoropyrimidine toxicities.

PMID:39887719 | DOI:10.1002/cpt.3567

Expert Rev Clin Immunol. 2025 Jan 31. doi: 10.1080/1744666X.2025.2461584. Online ahead of print.

ABSTRACT

INTRODUCTION: Inflammatory bowel diseases (IBDs), comprised of ulcerative colitis (UC) and Crohn's disease (CD), are chronic inflammatory diseases of the gastrointestinal tract. Clinicians and patients must vigilantly manage these complex diseases over the course of the patient's lifetime to mitigate risks of the disease, surgical complications, progression to neoplasia, and complications from medical or surgical therapies. Over the past several decades, the armamentarium of IBD therapeutics has expanded; now with biologics and advanced small molecules complementing conventional drugs such as aminosalicylates, corticosteroids and thiopurines. Significant attention has been paid to the potential of precision medicine to assist clinicians in tailoring therapeutics based on patients' genetic signatures to maximize therapeutic benefit while minimizing adverse effects.

AREAS COVERED: In this paper, we review the published literature on genetic polymorphisms relevant to each class of IBD therapeutics.

EXPERT OPINION: Finally, we envision a paradigm shift in IBD research toward an omics-based network analysis approach. Through global collaboration, organization and goal setting, we predict the next decade of IBD research will revolutionize existing disease frameworks by developing precise molecular diagnoses, validated biomarkers, predictive models and novel molecularly targeted therapeutics.

PMID:39885730 | DOI:10.1080/1744666X.2025.2461584

Drug Metab Dispos. 2025 Jan;53(1):100011. doi: 10.1124/dmd.124.001923. Epub 2024 Nov 22.

ABSTRACT

Many factors cause interperson variability in the activity and expression of the cytochrome P450 (CYP) drug-metabolizing enzymes in the liver, leading to variable drug exposure and treatment outcomes. Several liver-enriched transcription factors are associated with CYP expression, with estrogen receptor α (ESR1) and constitutive androstane receptor (CAR or NR1I3) being the 2 top factors. ESR1 and NR1I3 undergo extensive alternative splicing that results in numerous splice isoforms, but how these splice isoforms associate with CYP expression is unknown. Here, we quantified 18 NR1I3 splice isoforms and the 3 most abundant ESR1 isoforms in 260 liver samples derived from African Americans (n = 125) and European Americans (n = 135). Our results showed variable splice isoform populations in the liver for both NR1I3 and ESR1. Multiple linear regression analyses revealed that compared with gene-level NR1I3, isoform-level NR1I3 expression better predicted the mRNA expression of most CYPs and 3 UDP-glucuronosyltransferases (UGTs), whereas ESR1 isoforms improved predictive models for the UGTs and CYP2D6 but not for most CYPs. Also, different NR1I3 isoforms were associated with different CYPs, and the associations varied depending on sample ancestry. Surprisingly, noncanonical NR1I3 isoforms having retained introns (introns 2 or 6) were abundantly expressed and associated with the expression of most CYPs and UGTs, whereas the reference isoform (NR1I3-205) was only associated with CYP2D6. Moreover, NR1I3 isoform diversity increased during the differentiation of induced pluripotent stem cells to hepatocytes, paralleling increasing CYP expression. These results suggest that isoform-level transcription factor expression may help to explain variation in CYP or UGT expression between individuals. SIGNIFICANCE STATEMENT: We quantified 18 NR1I3 splice isoforms and the 3 most abundant ESR1 splice isoforms in 260 liver samples derived from African American and European American donors and found variable NR1I3 and ESR1 splice isoform expression in the liver. Multiple linear regression analysis showed that, compared with gene-level expression, isoform-level expression of NR1I3 and ESR1 better predicted the mRNA expression of some cytochrome P450s and UDP-glucuronosyltransferases, highlighting the importance of isoform-level analyses to enhance our understanding of gene transcriptional regulatory networks controlling the expression of drug-metabolizing enzymes.

PMID:39884819 | DOI:10.1124/dmd.124.001923

Drug Metab Dispos. 2025 Jan;53(1):100023. doi: 10.1124/dmd.124.001916. Epub 2024 Nov 23.

ABSTRACT

Remimazolam (Byfavo, Acacia Pharma), a recent Food and Drug Administration-approved ester-linked benzodiazepine, offers advantages in sedation, such as rapid onset and predictable duration, making it suitable for broad anesthesia applications. Its favorable pharmacological profile is primarily attributed to rapid hydrolysis, the primary metabolism pathway for its deactivation. Thus, understanding remimazolam hydrolysis determinants is essential for optimizing its clinical use. This study aimed to identify the enzyme(s) and tissue(s) responsible for remimazolam hydrolysis and to evaluate the influence of genetic polymorphisms and drug-drug interactions on its hydrolysis in the human liver. An initial incubation study with remimazolam and PBS, human serum, and the S9 fractions of human liver and intestine demonstrated that remimazolam was exclusively hydrolyzed by human liver S9 fractions. Subsequent incubation studies utilizing a carboxylesterase inhibitor (bis(4-nitrophenyl) phosphate), recombinant human carboxylesterase 1 (CES1) and carboxylesterase 2 confirmed that remimazolam is specifically hydrolyzed by CES1 in human liver. Furthermore, in vitro studies with wild-type CES1 and CES1 variants transfected cells revealed that certain genetic polymorphisms significantly impair remimazolam deactivation. Notably, the impact of CES1 G143E was verified using individual human liver samples. Moreover, our evaluation of the drug-drug interactions between remimazolam and several other substrates/inhibitors of CES1-including simvastatin, enalapril, clopidogrel, and sacubitril-found that clopidogrel significantly inhibited remimazolam hydrolysis at clinically relevant concentrations, with CES1 genetic variants potentially influencing the interactions. In summary, CES1 genetic variants and its interacting drugs are crucial factors contributing to interindividual variability in remimazolam hepatic hydrolysis, holding the potential to serve as biomarkers for optimizing remimazolam use. SIGNIFICANCE STATEMENT: This investigation demonstrates that remimazolam is deactivated by carboxylesterase 1 (CES1) in the human liver, with CES1 genetic variants and drug-drug interactions significantly influencing its metabolism. These findings emphasize the need to consider CES1 genetic variability and potential drug-drug interactions in remimazolam use, especially in personalized pharmacotherapy to achieve optimal anesthetic outcomes.

PMID:39884809 | DOI:10.1124/dmd.124.001916

Mol Biol Cell. 2025 Jan 29:mbcE24110512. doi: 10.1091/mbc.E24-11-0512. Online ahead of print.

ABSTRACT

Rare inherited diseases caused by mutations in the copper transporters SLC31A1 (CTR1) or ATP7A induce copper deficiency in the brain, causing seizures and neurodegeneration in infancy through poorly understood mechanisms. Here, we used multiple model systems to characterize the molecular mechanisms by which neuronal cells respond to copper deficiency. Targeted deletion of CTR1 in neuroblastoma cells produced copper deficiency that produced a metabolic shift favoring glycolysis over oxidative phosphorylation. Proteomic and transcriptomic analysis of CTR1 KO cells revealed simultaneous upregulation of mTORC1 and S6K signaling and reduced PERK signaling. Patterns of gene and protein expression and pharmacogenomics show increased activation of the mTORC1-S6K pathway as a pro-survival mechanism, ultimately resulting in increased protein synthesis. Spatial transcriptomic profiling of Atp7aflx/Y:: Vil1Cre/+ mice identified upregulated protein synthesis machinery and mTORC1-S6K pathway genes in copper-deficient Purkinje neurons in the cerebellum. Genetic epistasis experiments in Drosophila demonstrated that copper deficiency dendritic phenotypes in class IV neurons are improved or rescued by increased S6k expression or 4E-BP1 (Thor) RNAi, while epidermis phenotypes are exacerbated by Akt, S6k, or raptor RNAi. Overall, we demonstrate that increased mTORC1-S6K pathway activation and protein synthesis is an adaptive mechanism by which neuronal cells respond to copper deficiency.

PMID:39878654 | DOI:10.1091/mbc.E24-11-0512

Front Pharmacol. 2025 Jan 14;15:1516469. doi: 10.3389/fphar.2024.1516469. eCollection 2024.

ABSTRACT

Pharmacogenomics (PGx) is a powerful tool for clinical optimization of drug efficacy and safety. However, due to many factors affecting drugs in the real world, PGx still accounts for a small proportion of actual clinical application scenarios. Therefore, based on the information software, pharmacists use their professional advantages to integrate PGx into all aspects of pharmaceutical care, which is conducive to promoting the development of personalized medicine. In this paper, the establishment of an information software platform is summarized for the optimization of a personalized medication program based on PGx. Taking colorectal cancers (CRC) as an example, this paper also discusses the role of PGx in different working modes and participation in drug management of CRC patients by pharmacists with the help of information systems. Finally, we summarized the recommendations of different PGx guidelines to provide reference for the follow-up personalized pharmaceutical care.

PMID:39877392 | PMC:PMC11772163 | DOI:10.3389/fphar.2024.1516469

Clin Transplant. 2025 Feb;39(2):e70092. doi: 10.1111/ctr.70092.

ABSTRACT

Since 1987, King Chulalongkorn Memorial Hospital (KCMH) has performed a substantial number of heart transplants as a specific therapy for advanced-stage heart failure. This descriptive study aimed to analyze post-transplant survival in the recent era compared to earlier periods and examine the pharmacogenetics of related immunosuppressants. Data from all recipients who underwent heart transplants from 1987 to 2021 were retrospectively retrieved from the electronic medical record. The genotypes of relevant pharmacogenes were analyzed in recipients who were alive during the enrollment period. Kaplan-Meier analysis revealed improved overall survival rates in the recent era compared to the past. Dilated cardiomyopathy was identified as the most common pretransplant diagnosis, while infection remained the leading cause of mortality. In conclusion, the findings demonstrate significant advancements in the quality of heart transplantation in Thailand. Future studies are warranted to explore the correlation between pharmacogenetic variations identified in this study and subsequent clinical outcomes, with a focus on genetic-guided treatment to optimize patient care.

PMID:39876635 | DOI:10.1111/ctr.70092

Asian Pac J Cancer Prev. 2025 Jan 1;26(1):5-15. doi: 10.31557/APJCP.2025.26.1.5.

ABSTRACT

Doxorubicin, a widely used anthracycline antibiotic, has been a cornerstone in cancer chemotherapy since the 1960s. In addition to doxorubicin, anthracycline chemotherapy medications include daunorubicin, idarubicin, and epirubicin. For many years, doxorubicin has been the chemotherapy drug of choice for treating a broad variety of cancers. Despite its efficacy, doxorubicin therapy is hindered by serious side effects, primarily cardiotoxicity, and the challenges of drug resistance. Recent research has focused on optimizing doxorubicin's therapeutic index by developing cardioprotective strategies, such as dexrazoxane, and utilizing non-invasive monitoring techniques to reduce cardiac risk. To counteract drug resistance, innovative formulations like nanoparticle-based delivery systems, enhance targeted drug delivery and overcome cellular resistance mechanisms. Furthermore, using combination approaches involving immunotherapy, photodynamic therapy, and genetic modulation, offer promising synergies to maximize tumor eradication. Personalized approaches, supported by pharmacogenomics and predictive biomarkers, are enhancing individualized treatment regimens, aiming to increase effectiveness and minimize toxicity. Future research on doxorubicin focuses on developing advanced drug delivery systems, such as nanoparticle and liposomal formulations, to enhance targeted delivery, minimize systemic toxicity, and improve therapeutic precision. Efforts are also underway to design combination therapies that integrate doxorubicin with immunotherapies, photodynamic approaches, and gene-based treatments, aiming to overcome resistance and increase tumor-specific effects. These advancements signify a transition toward more personalized and effective doxorubicin-based cancer therapies, prioritizing reduced side effects and improved patient outcomes. This article focusses on the ongoing innovations aimed at maximizing the therapeutic potential of doxorubicin while addressing its limitations.

PMID:39873980 | DOI:10.31557/APJCP.2025.26.1.5

Clin Transl Sci. 2025 Feb;18(2):e70059. doi: 10.1111/cts.70059.

ABSTRACT

Tramadol, the 41st most prescribed drug in the United States in 2021 is a prodrug activated by CYP2D6, which is highly polymorphic. Previous studies showed enzyme-inhibitor affinity varied between different CYP2D6 allelic variants with dextromethorphan and atomoxetine metabolism. However, no study has compared tramadol metabolism in different CYP2D6 alleles with different CYP2D6 inhibitors. We hypothesize that the inhibitory effects of CYP2D6 inhibitors on CYP2D6-mediated tramadol metabolism are inhibitor- and CYP2D6-allele-specific. We performed comparative analyses of CYP2D6*1, CYP2D6*2, CYP2D6*10, and CYP2D6*17 using recombinant enzymes to metabolize tramadol to O-desmethyltramadol, measured via UPLC-MS/MS. The Michaelis constant (Km) and maximum velocity (Vmax) for each CYP2D6 allele, and IC50 values for different inhibitors were determined by nonlinear regression analysis. Intrinsic clearance was calculated as Vmax/Km. The intrinsic clearance of tramadol was almost double for CYP2D6*2 (180%) but was much lower for CYP2D6*10 and *17 (20% and 10%, respectively) compared to CYP2D6*1. The inhibitor potencies (defined by Ki) for the various inhibitors for the CYP2D6*1 allele were quinidine > terbinafine > paroxetine ≈ duloxetine >>bupropion. CYP2D6*2 showed the next greatest inhibition, with Ki ratios compared to CYP2D6*1 ranging from 0.96 to 3.87. For each inhibitor tested, CYP2D6*10 and CYP2D6*17 were more resistant to inhibition than CYP2D6*1 or CYP2D6*2, with most Ki ratios in the 3-9 range. Three common CYP2D6 allelic variants showed different metabolic capacities toward tramadol and genotype-dependent inhibition compared to CYP2D6*1. Further studies are warranted to understand the clinical consequences of inhibitor and CYP2D6 genotype-dependent drug-drug interactions on tramadol bioactivation.

PMID:39870079 | DOI:10.1111/cts.70059

Clin Pharmacol Ther. 2025 Jan 27. doi: 10.1002/cpt.3552. Online ahead of print.

ABSTRACT

Clopidogrel, an anti-platelet drug, is used to prevent thrombosis after percutaneous coronary intervention. Clopidogrel resistance results in recurring ischemic events, with African Americans (AA) suffering disproportionately. The aim of this study was to discover novel biomarkers of clopidogrel resistance in African Americans using genome and transcriptome data. We conducted a genome-wide association study (GWAS), including local ancestry adjustment, in 141 AA on clopidogrel to identify genetic associations with high on-treatment platelet reactivity (HTPR), with validation of genome-wide significant and suggestive loci in an independent cohort of AA clopidogrel patients (N = 823) from the Million Veteran's Program (MVP) along with in vitro functional analysis. We performed differential gene expression (DGE) analysis in whole blood to identify transcriptomic predictors of response, followed by functional validation in MEG-01 cells. GWAS identified one signal on Chromosome 7 as significantly associated with increasing risk of HTPR. The lead single-nucleotide polymorphism (SNP), rs7807369, within thrombospondin 7A (THSD7A) was associated with an increased risk of HTPR (odds ratio (OR) = 4.02, P = 4.56 × 10-9). Higher THSD7A gene expression was associated with HTPR in an independent cohort of clopidogrel-treated patients (P = 0.004) and carrying a risk allele showed increased gene expression in primary human endothelial cells. Notably, the CYP2C19*2 variants showed no association with clopidogrel response in the discovery or MVP cohorts. DGE analysis identified an association with decreased LAIR1 and AP3B2 expression to HTPR. LAIR1 knockdown in MEG-01 cells resulted in increased expression of SYK and AKT1, suggesting an inhibitory role of LAIR1 in the Glycoprotein VI pathway. In summary, these findings suggest that other variants and genes outside of CYP2C19 star alleles play an important role in clopidogrel response in AA.

PMID:39868839 | DOI:10.1002/cpt.3552

Am J Med Genet B Neuropsychiatr Genet. 2025 Jan 27:e33024. doi: 10.1002/ajmg.b.33024. Online ahead of print.

ABSTRACT

Pharmacogenetic studies involving Carboxylesterase 1 (CES1), Latrophilin-3 (LPHN3), and Catechol-O-methyltransferase (COMT) revealed individual differences regarding therapeutic response in children with attention deficit hyperactivity disorder (ADHD) under methylphenidate (MPH) treatment. This study aimed to evaluate MPH's association with the adverse effect status in children and its relationship with CES1, LPHN3, and COMT in the Turkish population. The study included 102 children and adolescents with ADHD, who were categorized as responders, or the adverse effect group based on their treatment response. The Naranjo Adverse Drug Reaction Probability Scale evaluated the presence and severity of adverse effects. Saliva sample was taken from the patients and genotype distribution of CES1 rs3815583, CES1 rs2307227, LPHN3 rs6551665, LPHN3 rs1947274, LPHN3 rs6858066, LPHN3 rs2345039, and COMT rs4680 were examined. In the adverse effect group, instances of carrying the GG genotype in CES1 rs2307227, having G vs. T genotype and GG vs. GT were significantly higher. In LPHN3 rs2345039, carrying the C genotype vs. G was associated with a serious adverse effect. In COMT rs4680, individuals with the AA or GG genotype were significantly higher in the adverse effect group. Our study suggests a relationship between genetic polymorphisms and the side effect status in children receiving MPH.

PMID:39868802 | DOI:10.1002/ajmg.b.33024

bioRxiv [Preprint]. 2025 Jan 13:2025.01.10.632500. doi: 10.1101/2025.01.10.632500.

ABSTRACT

The Arabian Peninsula is considered the initial site of historic human migration out of Africa. The modern-day indigenous Arabians are believed to be the descendants who remained from the ancient split of the migrants into Eurasia. Here, we investigated how the population history and cultural practices such as endogamy have shaped the genetic variation of the Saudi Arabians. We genotyped 3,352 individuals and identified twelve genetic sub-clusters that corresponded to the geographical distribution of different tribal regions, differentiated by distinct components of ancestry based on comparisons to modern and ancient DNA references. These sub-clusters also showed variation across ranges of the genome covered in runs of homozygosity, as well as differences in population size changes over time. Using 25,488,981 variants found in whole genome sequencing data (WGS) from 302 individuals, we found that the Saudi tend to show proportionally more deleterious alleles than neutral alleles when compared to Africans/African Americans from gnomAD (e.g. a 13% increase of deleterious alleles annotated by AlphaMissense between 0.5 -5% frequency in Saudi, compared to 7% decrease of the benign alleles; P < 0.001). Saudi sub-clusters with greater inbreeding and lower effective population sizes showed greater enrichment of deleterious alleles as well. Additionally, we found that approximately 10% of the variants discovered in our WGS data are not observed in gnomAD; these variants are also enriched with deleterious annotations. To accelerate studying the population-enriched deleterious alleles and their health consequences in this population, we made available the allele frequency estimates of 25,488,981 variants discovered in our samples. Taken together, our results suggest that Saudi's population history impacts its pattern of genetic variation with potential consequences to the population health. It further highlights the need to sequence diverse and unique populations so to provide a foundation on which to interpret medical-and pharmaco-genomic findings from these populations.

PMID:39868174 | PMC:PMC11761371 | DOI:10.1101/2025.01.10.632500

Front Mol Neurosci. 2025 Jan 10;17:1503396. doi: 10.3389/fnmol.2024.1503396. eCollection 2024.

ABSTRACT

Multiple sclerosis (MS) affects 2.8 million people worldwide. Although the cause is unknown, various risk factors might be involved. MS involves the immune system attacking the central nervous system's myelin sheath, leading to neuron damage. This study used a cuprizone (CPZ)-intoxicated mouse model to simulate MS's demyelination/remyelination process. It evaluated the molecular, histological, and behavioral effects of vanillic acid (VA), a natural phenolic acid, alone and with Ibudilast (IBD), a clinically tested MS medication. Mice were divided into a control group (regular chow) and a CPZ group (0.3% cuprizone chow for 5 consecutive weeks). During remyelination, the CPZ group was split into four groups: no therapy, 10 mg/kg of IBD, 30 mg/kg of VA, and combined, each treated for 4 weeks. Behavioral, biochemical, molecular, and histopathological tests occurred in the 5th week (demyelination), 7th (early remyelination), and 9th (late remyelination). Cognitive assessments were at weeks 5 and 9. VA enhanced motor, coordination, and cognitive impairments in CPZ-intoxicated mice and improved histopathological, molecular, and biochemical features during early remyelination. IBD improved behavioral abnormalities across all tests, but combined therapy showed no significant difference from single therapies. Further investigations are necessary to understand VA's mechanisms and potential as an MS treatment.

PMID:39866908 | PMC:PMC11760597 | DOI:10.3389/fnmol.2024.1503396

Curr Neuropharmacol. 2025 Jan 24. doi: 10.2174/011570159X349579241231080602. Online ahead of print.

ABSTRACT

INTRODUCTION: Glucagon-Like Peptide-1 Receptor (GLP1R) agonists have become widespread anti-obesity/diabetes pharmaceuticals in the United States.

AIM: This article aimed to provide our current knowledge on the plausible mechanisms linked to the role of Ozempic (Semaglutide), which is generalized as one of the anti-addiction compounds.

METHODS: The effects of GLP1R agonists in Alcohol Use Disorder (AUD) and substance use disorder (SUD) are mediated, in part, through the downregulation of dopamine signaling. We posit that while GLP1R agonism could offer therapeutic advantages in hyperdopaminergia, it may be detrimental in patients with hypodopaminergia, potentially leading to long-term induction of Suicidal Ideation (SI). The alleged posit of GLP1 agonists to induce dopamine homeostasis is incorrect. This study refined 31 genes based on the targets of Ozempic, GLP1R, and related enzymes for SI and 10 genes of the Genetic Addiction Risk Score (GARS) test. STRING-MODEL refined 29 genes, and further primary analyses indicated associations of GLP1R with DRD3, BDNF, CREB1, CRH, IL6, and DPP4.

RESULTS: In-depth silico enrichment analysis revealed an association between candidate genes and depressive phenotypes linked with dopaminergic signaling. Finally, through primary and in-depth silico analyses, we demonstrated multiple findings supporting that GLP1R agonists can induce depression phenotypes.

CONCLUSION: Our findings suggest that associated polymorphisms seem to have overlapping effects with addictive behaviors of Reward Deficiency Syndrome (RDS) and dopamine regulation. Consequently, GLP1R agonists may represent a double-edged sword, potentially triggering both antiaddictive effects and SI by exacerbating depressive phenotypes. Thus, we encourage the scientific community to perform further empirical clinical studies to confirm this proposed pathway.

PMID:39865816 | DOI:10.2174/011570159X349579241231080602