CYP2D6 Research Articles

Haplotype phasing of CYP2D6: an allelic ratio method using Agena MassARRAY data

Pharmacogenomics aims to use the genetic information of an individual to personalize drug prescribing. There is evidence that pharmacogenomic testing before prescription may prevent adverse drug reactions, increase efficacy, and reduce cost of treatment. CYP2D6 is a key pharmacogene of relevance to multiple therapeutic areas. Indeed, there are prescribing guidelines available for medications based on CYP2D6 enzyme activity as deduced from CYP2D6 genetic data. The Agena MassARRAY system is a cost-effective method of detecting genetic variation that has been clinically applied to other genes. However, its clinical application to CYP2D6 has to date been limited by weaknesses such as the inability to determine which haplotype was present in more than one copy for individuals with more than two copies of the CYP2D6 gene. We report application of a new protocol for CYP2D6 haplotype phasing of data generated from the Agena MassARRAY system. For samples with more than two copies of the CYP2D6 gene for which the prior consensus data specified which one was present in more than one copy, our protocol was able to conduct CYP2D6 haplotype phasing resulting in 100% concordance with the prior data. In addition, for three reference samples known to have more than two copies of CYP2D6 but for which the exact number of CYP2D6 genes was unknown, our protocol was able to resolve the number for two out of the three of these, and estimate the likely number for the third. Finally, we demonstrate that our method is applicable to CYP2D6 hybrid tandem configurations.

Pharmacogenomics and non-genetic factors affecting drug response in autism spectrum disorder in Thai and other populations: current evidence and future implications.

Autism spectrum disorder (ASD) may affect family and social life profoundly. Although there is no selective pharmacotherapy for ASD, the Food and Drug Administration (FDA) has recommended risperidone/aripiprazole to treat the associated symptoms of ASD, such as agitation/irritability. Strong associations of some pharmacokinetic/pharmacodynamic gene variants, e.g., CYP2D6 and DRD2, with risperidone-induced hyperprolactinemia have been found in children with ASD, but such strong genetic associations have not been found directly for aripiprazole in ASD. In addition to pharmacogenomic (PGx) factors, drug-drug interactions (DDIs) and possibly cumulative effects of DDIs and PGx may affect the safety or effectiveness of risperidone/aripiprazole, which should be assessed in future clinical studies in children with ASD. Reimbursement, knowledge, and education of healthcare professionals are the key obstacles preventing the successful implementation of ASD pharmacogenomics into routine clinical practice. The preparation of national and international PGx-based dosing guidelines for risperidone/aripiprazole based on robust evidence may advance precision medicine for ASD.

Effect of the NFIB rs28379954 T>C polymorphism on CYP2D6-catalyzed metabolism of solanidine.

Cytochrome P450 2D6 (CYP2D6) is important for metabolism of 20%-25% of all clinically used drugs. Many known genetic variants contribute to the large interindividual variability in CYP2D6 metabolism, but much is still unexplained. We recently described that nuclear factor 1B (NFIB) regulates hepatic CYP2D6 expression with the minor allele of NFIB rs28379954 T>C significantly increasing CYP2D6-mediated risperidone metabolism. In this study, we investigated the effect of NFIB T>C on metabolism of solanidine, a dietary CYP2D6 substrate. Analyses of solanidine and metabolites (M414, M416, and M444) were performed by ultra-high performance liquid chromatography-high-resolution mass spectrometry in a cohort of 463 CYP2D6-genotyped patients of which with 58 (12.5%) carried NFIB TC (n = 56) or CC (n = 2). Increased metabolism of solanidine was found in CYP2D6 normal metabolizers (NMs; n = 258, 55.7%) carrying the NFIB C variant (n = 27, 5.8%) with 2.83- and 3.38-fold higher M416-to-solanidine (p = 0.039) and M444-to-solanidine (p = 0.046) ratios, respectively, whereas this effect was not significant among intermediate metabolizers (n = 166, 35.9%) (p ≥ 0.09). Importantly, no effect of the NFIB polymorphism on solanidine metabolism was seen in TC or CC carriers lacking CYP2D6 activity (poor metabolizers, n = 30, 6.5%, p ≥ 0.74). Furthermore, the NFIB polymorphism significantly explained variability in solanidine metabolism (M414 p = 0.013, M416 p = 0.020, and M416 and M444 p = 0.009) in multiple linear regression models for each metabolic ratio in the entire population, correcting for covariates (including CYP2D6 genotypes). Thus, the study confirms the effect of NFIB in regulating CYP2D6 activity, suggesting an about 200% increase in CYP2D6-mediated clearance in NMs being NFIB CT or CC carriers, comprising around 6% of Europeans.

The genomic landscape of CYP2D6 variation in the Indian population.

Aim: The CYP2D6 gene is highly polymorphic, causing large interindividual variability in the metabolism of several clinically important drugs. Materials & methods: The authors investigated the diversity and distribution of CYP2D6 alleles in Indians using whole genome sequences (N=1518). Functional consequences were assessed using pathogenicity scores and molecular dynamics simulations. Results: The analysis revealed population-specific CYP2D6 alleles (*86, *7, *111, *112, *113, *99) and remarkable differences in variant and phenotype frequencies with global populations. The authors observed that one in three Indians could benefit from a dose alteration for psychiatric drugs with accurate CYP2D6 phenotyping. Molecular dynamics simulations revealed large conformational fluctuations, confirming the predicted reduced function of *86 and *113 alleles. Conclusion: The findings emphasize the utility of comprehensive CYP2D6 profiling for aiding precision public health.

Solanidine is a sensitive and specific dietary biomarker for CYP2D6 activity

BackgroundIndividual assessment of CYP enzyme activities can be challenging. Recently, the potato alkaloid solanidine was suggested as a biomarker for CYP2D6 activity. Here, we aimed to characterize the sensitivity and specificity of solanidine as a CYP2D6 biomarker among Finnish volunteers with known CYP2D6 genotypes.ResultsUsing non-targeted metabolomics analysis, we identified 9152 metabolite features in the fasting plasma samples of 356 healthy volunteers. Machine learning models suggested strong association between CYP2D6 genotype-based phenotype classes with a metabolite feature identified as solanidine. Plasma solanidine concentration was 1887% higher in genetically poor CYP2D6 metabolizers (gPM) (n = 9; 95% confidence interval 755%, 4515%; P = 1.88 × 10–11), 74% higher in intermediate CYP2D6 metabolizers (gIM) (n = 89; 27%, 138%; P = 6.40 × 10–4), and 35% lower in ultrarapid CYP2D6 metabolizers (gUM) (n = 20; 64%, − 17%; P = 0.151) than in genetically normal CYP2D6 metabolizers (gNM; n = 196). The solanidine metabolites m/z 444 and 430 to solanidine concentration ratios showed even stronger associations with CYP2D6 phenotypes. Furthermore, the areas under the receiver operating characteristic and precision–recall curves for these metabolic ratios showed equal or better performances for identifying the gPM, gIM, and gUM phenotype groups than the other metabolites, their ratios to solanidine, or solanidine alone. In vitro studies with human recombinant CYP enzymes showed that solanidine was metabolized mainly by CYP2D6, with a minor contribution from CYP3A4/5. In human liver microsomes, the CYP2D6 inhibitor paroxetine nearly completely (95%) inhibited the metabolism of solanidine. In a genome-wide association study, several variants near the CYP2D6 gene associated with plasma solanidine metabolite ratios.ConclusionsThese results are in line with earlier studies and further indicate that solanidine and its metabolites are sensitive and specific biomarkers for measuring CYP2D6 activity. Since potato consumption is common worldwide, this biomarker could be useful for evaluating CYP2D6-mediated drug–drug interactions and to improve prediction of CYP2D6 activity in addition to genotyping.

A consideration of CYP2D6 genetic variations in the Ghanaian population as a potential 'culprit' for the tramadol 'abuse crisis'.

Cytochrome P450 2D6 is involved in the metabolism of several important medicines including opioids. Variations in CYP2D6 have been implicated in drug response and according to the Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2D6, dosing for CYP2D6 substrates should be based on variants carried by individuals. Although CYP2D6 variations in Ghana had been previously recorded, not all variants have been reported in the Ghanaian population. In this exploratory study we set to investigate certain unreported variations in the Ghanaian population in addition to the previously reported ones and use that to understand the tramadol 'abuse' crisis that is currently being experienced in Ghana. This study employed a convenience sampling approach to include 106 unrelated participants who were recruited as part of the PHARMABIOME project. We successfully genotyped 106 samples using Iplex GOLD SNP genotyping protocol after extracting DNA from these individuals. Allele and diplotype frequencies were undertaken by counting from observed genotypes. Comparison of alleles reported from various studies were done. Unreported alleles such as *3, *9 and *41 which are classified as no function and decreased function were observed in our study cohort. In addition, variants such as (*1, *2, *4, *5, *10, *17 and *29 were observed with different frequencies. Our study showed 26% representation of intermediate metabolizers (IM) and 2% poor metabolizers (PM) in the study population. The implications for informal sector workers who use tramadol for recreational purposes, is that IMs and PMs will overdose as they may have reduced analgesic effects which will translate into increased risks of unforeseen adverse events. We therefore propose that CYP2D6 should be considered in opioid dosage while making use of these observed variations to implement new approaches to tackle the tramadol 'abuse crisis' in Ghana.

Water Exchange from the Buried Binding Sites of Cytochrome P450 Enzymes 1A2, 2D6, and 3A4 Correlates with Conformational Fluctuations.

Human cytochrome P450 enzymes (CYPs) are critical for the metabolism of small-molecule pharmaceuticals (drugs). As such, the prediction of drug metabolism by and drug inhibition of CYP activity is an important component of the drug discovery and design process. Relative to the availability of a wide range of experimental atomic-resolution CYP structures, the development of structure-based CYP activity models has been limited. To better characterize the role of CYP conformational fluctuations in CYP activity, we perform multiple microsecond-scale all-atom explicit-solvent molecular dynamics (MD) simulations on three CYP isoforms, 1A2, 2D6, and 3A4, which together account for the majority of CYP-mediated drug metabolism. The MD simulations employ a variety of positional restraints, ranging from keeping all CYP atoms close to their experimentally determined coordinates to allowing full flexibility. We find that, with full flexibility, large fluctuations in the CYP binding sites correlate with efficient water exchange from these buried binding sites. This is especially true for 1A2, which, when restrained to its crystallographic conformation, is unable to exchange water between the binding site and bulk solvent. These findings imply that, in addition to crystal structures, a representative ensemble of conformational states ought to be included when developing structure-based CYP activity models.

Risperidone plasma level, and its correlation with CYP2D6 gene polymorphism, clinical response and side effects in chronic schizophrenia patients

BackgroundTo explore the influence of CYP2D6 genetic polymorphism on risperidone metabolism, thereby affecting risperidone’s effects and safeties in patients with chronic schizophrenia.MethodsSixty-nine subjects with chronic schizophrenia treated with risperidone were recruited. CYP2D6 genotypes was determined using targeted sequencing and translated into phenotype using activity system. Risperidone plasma concentrations were measured using HPLC. Positive and Negative Symptom Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) were used to evaluate the existence and severity of psychiatric symptoms, Barnes Akathisia Scale (BAS) and Extrapyramidal Symptom Rating Scale (ESRS) for neurological side effects. Metabolic and endocrine status assess were also included.ResultsThe plasma drug concentrations varied hugely among individuals. Intermediate metabolizer (IM) group had higher plasma levels of RIP and dose corrected RIP concentration, RIP/9-OH-RIP ratio and C/D ratio than normal metabolizer (NM) group (p < 0.01). There was no statistic difference between responders and non-responders in dose-adjusted plasma concentrations and ratios of RIP/9-OH-RIP and C/D. The occurrence of EPS was related to active moiety levels in 4th week (p < 0.05). The prolactin (PRL) levels in two follow-ups were both significantly higher than baseline (p < 0.01). PRL change from baseline to week 4 and week 8 were both positively associated with active moiety concentration detected in week 4 (p < 0.05).ConclusionsThe risperidone plasma levels have great inter- and intraindividual variations, and are associated with the CYP2D6 phenotypes, as well as the changes in serum prolactin in patients diagnosed with chronic schizophrenia.

Population Pharmacokinetic Analysis of Atomoxetine and its Metabolites in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder.

Atomoxetine (ATX) is a non-stimulant used to treat attention-deficit/hyperactivity disorder (ADHD) and systemic exposure is highly variable due to polymorphic cytochrome P450 2D6 (CYP2D6) activity. The objective of this study was to characterize the time course of ATX and metabolites (4-hydroxyatomoxetine (4-OH); N-desmethylatomoxetine (NDA); and 2-carboxymethylatomoxetine (2-COOH)) exposure following oral ATX dosing in children with ADHD to support individualized dosing. A nonlinear mixed-effect modeling approach was used to analyze ATX, 4-OH, and NDA plasma and urine, and 2-COOH urine profiles obtained over 24-72 hours from children with ADHD (n = 23) following a single oral ATX dose. Demographics and CYP2D6 activity score (AS) were evaluated as covariates. Simulations were performed to explore the ATX dosing in subjects with various CYP2D6 AS. A simultaneous pharmacokinetic modeling approach was used in which a model for ATX, 4-OH, and NDA in plasma and urine, and 2-COOH in urine was developed. Plasma ATX, 4-OH, and NDA were modeled using two-compartment models with first-order elimination. CYP2D6 AS was a significant determinant of ATX apparent oral clearance (CL/F), fraction metabolized to 4-OH, and systemic exposure of NDA. CL/F of ATX varied almost 7-fold across the CYP2D6 AS groups: AS 2: 20.02 L/hour; AS 1: 19.00 L/hour; AS 0.5: 7.47 L/hour; and AS 0: 3.10 L/hour. The developed model closely captures observed ATX, 4-OH, and NDA plasma and urine, and 2-COOH urine profiles. Application of the model shows the potential for AS-based dosing recommendations for improved individualized dosing.

Functional maturation of cytochromes P450 3A4 and 2D6 relies on GAPDH- and Hsp90-Dependent heme allocation

Cytochrome P450 3A4 and 2D6 (EC 1.14.13.97 and 1.14.14; CYP3A4 and 2D6) are heme-containing enzymes that catalyze the oxidation of a wide number of xenobiotic and drug substrates and thus broadly impact human biology and pharmacologic therapies. Although their activities are directly proportional to their heme contents, little is known about the cellular heme delivery and insertion processes that enable their maturation to functional form. We investigated the potential involvement of GAPDH and chaperone Hsp90, based on our previous studies linking these proteins to intracellular heme allocation. We studied heme delivery and insertion into CYP3A4 and 2D6 after they were transiently expressed in HEK293T and GlyA CHO cells or when naturally expressed in HEPG2 cells in response to rifampicin, and also investigated their associations with GAPDH and Hsp90 in cells. The results indicate that GAPDH and its heme binding function is involved in delivery of mitochondria-generated heme to apo-CYP3A4 and 2D6, and that cell chaperone Hsp90 is additionally involved in driving their heme insertions. Uncovering how cells allocate heme to CYP3A4 and 2D6 provides new insight on their maturation process and how this may help to regulate their functions in health and disease.

Leveraging in Vitro Models for Clinically Relevant Rare CYP2D6 Variants in Pharmacogenomics.

Cytochrome P450 2D6 (CYP2D6) is responsible for the metabolism of up to 20% of small-molecule drugs and therefore, may impact the safety and efficacy of medicines in broad therapeutic areas. CYP2D6 is highly polymorphic, and the frequency of variants can differ across racial and ethnic populations, significantly affecting enzymatic function and drug metabolism. However, rare variants of CYP2D6 present a unique challenge for academia, industry, and regulatory agencies alike due to the lack of feasibility of characterizing their clinical relevance in clinical trials, particularly in variants that exhibit population-specific frequencies in racial and ethnic groups that are poorly represented in clinical trials. Despite significant advancement in pharmacogenomics, the substrate specificity and related clinical relevance of these CYP2D6 rare variants remain largely unclear, and further efforts are warranted to characterize the burden of these variants on adverse drug reactions and drug efficacy. Thus, cell-based in vitro systems can be used to inform substrate-specific effects and the overall relevance of a rare variant. Liver microsomes, cell-based expression systems, ex vivo primary samples, and purified variant protein have all been used with various substrates to potentially predict the clinical impact of new substrates. In this review, we identify rare variants of CYP2D6 that demonstrate differences across races in prevalence and thus are often unassessed in clinical trials. Accordingly, we examine current pharmacogenomic in vitro models used to analyze the functional impact of these rare variants in a substrate-specific manner. SIGNIFICANCE STATEMENT: Variants of CYP2D6 play a clinically relevant role in drug metabolism, leading to potential safety and efficacy concerns. Although the influence of prevalent variants is often well characterized, rare variants are traditionally not included in clinical trials. This review captures the clinical relevance of rare variants in CYP2D6 by highlighting in vitro models that analyze their impact on the metabolism of CYP2D6 substrates.

Genetic prediction of antihyperglycemic drug targets and risk of epilepsy: a mendelian randomisation study

A connection between diabetes and an increased risk of epilepsy has been suggested by observational studies. Animal studies have also shown that antihyperglycemic drugs can improve seizures. However, it is unclear whether antihyperglycemic drugs have a causal role in epilepsy in humans. To investigate this potential causal relationship, a Mendelian randomisation study was conducted using International League Against Epilepsy data as the discovery set and FinnGen data as the replication set. It was discovered that three antidiabetic drug target genes, ETFDH, CYP21A2 and CYP2D6, were involved in the occurrence of epilepsy. In particular, ETFDH was identified as a target gene in both the discovery set (inverse variance weighting [IVW], odds ratio [OR] = 1.018, 95% confidence interval [CI], 1.004–1.033, p = 0.009) and replication set (IVW, OR = 1.074, 95% CI, 1.034–1.114, p = 0.00016), and CYP21A2 was identified in the discovery set (IVW, OR = 1.029, 95% CI, 1.005–1.053, p = 0.016) and replication set (IVW, OR = 1.057, 95% CI, 1.001–1.116, p = 0.045) as having a causal association with an increased risk of epilepsy. Conversely, the CYP2D6 gene was found to be a protective factor for epilepsy in both the discovery set (IVW, OR = 0.0984, 95% CI, 0.969–0.998, p = 0.025) and replication set (IVW, OR = 0.977, 95% CI, 0.955–1.000, p = 0.046). A search of DrugBank revealed that metformin, an anti-glucose drug, is an inhibitor of the ETFDH gene and may have a potential therapeutic effect on epilepsy.

Evaluation of linkage disequilibrium between CYP2D6 gene polymorphisms associated with breast cancer in women

Introduction: the CYP2D6 gene is highly polymorphic and is involved in the metabolism of a wide variety of drugs and xenobiotics. Three allelic variants of the gene (rs3892097, rs1065852 and rs28371725) have been studied in relation to breast cancer, but the degree of genetic linkage between them is unknown.Objetive: to test whether the three breast cancer-associated SNPs are inherited en bloc.Methods: genotypes of 280 SNPs of the CYP2D6 gene were obtained from the 1000Genomes database and linkage disequilibrium between the three breast cancer-associated SNPs and the other 277 SNPs in the gene was analysed. A threshold of r2= 0,7 was used to identify loci in linkage disequilibrium.Results: a strong correlation was found between rs3892097 and rs1065852 in Europe and Latin America. In addition, eleven polymorphisms with a high level of linkage were identified, four of which have a non-synonymous mutation effect.Conclusions: both polymorphisms could have a causal effect on breast cancer or that one of them is associated by linkage. Continuing to study both polymorphisms and considering the eleven new polymorphisms for analysis would be of relevance to deepen knowledge in relation to breast cancer in women

L-lysine supplementation attenuates experimental autoimmune hepatitis in a chronic murine model.

The incidence of autoimmune hepatitis (AIH) has increased significantly worldwide. The present study aims to explore the protective effect of L-lysine supplementation against AIH and to investigate its potential underlying mechanisms. A chronic experimental AIH mouse model was established by repeated tail vein injection of human cytochrome P450 2D6 (CYP2D6) plasmid. Starting from day 14 of the modeling, mice in the CYP2D6-AIH +L-lysine group were given 200 µl of purified water containing 10 mg/kg L-lysine by gavage until day27, once a day, and mice in the healthy control group and model group were given an equal volume of purified water by gavage. Our results showed that L-lysine supplementation partially reversed the liver injury mediated by CYP2D6 overexpression. These effects were consistent with the restraining impacts of L-lysine supplementation on decreasing pro-inflammatory cytokines expression level and CD4+ and CD8+ T lymphocytes infiltration, as well as curbing hepatic oxidative stress. Furthermore, L-lysine supplement relieved liver fibrosis in the context of AIH. In conclusion, L-lysine supplementation attenuates CYP2D6-induced immune liver injury in mice, which may serve as a novel nutrition support approach for AIH.

No drug-drug interactions between selective prolyl-tRNA synthetase inhibitor, bersiporocin, and pirfenidone or nintedanib in healthy participants.

Bersiporocin, a potent and selective prolyl-tRNA synthetase inhibitor, is expected to show a synergistic effect with pirfenidone or nintedanib in patients with idiopathic pulmonary fibrosis. To validate the combination therapy of bersiporocin with pirfenidone or nintedanib, a randomized, open-label, two-part, one-sequence, three-period, three-treatment study was designed to evaluate the effect of drug-drug interactions (DDI) regarding their pharmacokinetics, safety, and tolerability in healthy participants. In addition, the pharmacokinetic profiles of the newly formulated, enteric-coated bersiporocin tablet were evaluated after single and multiple administrations. The potential effects of cytochrome P450 2D6 (CYP2D6) genotyping on bersiporocin pharmacokinetics and DDI were also explored. In Part 1, participants were sequentially administered a single dose of pirfenidone 600 mg, a single dose of bersiporocin 150 mg followed by multiple doses, and bersiporocin in combination with pirfenidone. In Part 2, participants were sequentially administered a single dose of nintedanib 150 mg, multiple doses of bersiporocin 150 mg, and bersiporocin in combination with nintedanib. Forty-six participants completed the study. There was no significant pharmacokinetic DDI between bersiporocin, and pirfenidone or nintedanib. All adverse events (AEs) were mild to moderate and did not include serious AEs, suggesting bersiporocin alone or in combination therapy were well-tolerated. The newly formulated bersiporocin 150 mg tablet showed a moderate accumulation index. There was no significant difference in the pharmacokinetic profiles after administration of bersiporocin alone or in combination therapy between CYP2D6 phenotypes. In conclusion, there are no significant DDI regarding the pharmacokinetics, safety, and tolerability of bersiporocin administration with pirfenidone or nintedanib.

Dextromethorphan/Bupropion: A Novel Treatment for Patients With Major Depressive Disorder.

Major depressive disorder (MDD) affects millions of people and is the leading cause of disability worldwide. Patients report decreased quality of life and ability to perform activities of daily living. It is estimated that the current standard of care, which includes pharmacologic therapy with a selective serotonin reuptake inhibitor, is effective in 40%-60%. Additional treatment options are warranted. The combination of dextromethorphan (DEX) and bupropion (BUP) (Auveulty) was approved for treatment in 2022. This unique combination offers an interesting mechanism of action and favorable onset of action for patients with MDD. The mechanism of action of DEX-BUP when used in combination is unique. DEX is a noncompetitive N-methyl-d-aspartate receptor antagonist rapidly metabolized through the CYP450 2D6. BUP is an aminoketone and CYP2D6 inhibitor, which results in increased plasma levels of DEX through competitive CYP2D6 inhibition. In a phase 2 clinical study, the efficacy of DEX-BUP was compared with BUP alone in patients with clinically diagnosed MDD. At baseline, participants had moderate-to-severe depression using the Montgomery-Asberg Depression Rating Scale (MADRS) and Clinical Global Impressions Severity (CGI-S) scales. There was a significant overall reduction in MADRS and CGI-S scores in the treatment group compared with the BUP monotherapy with improvement observed as early as week 1 of treatment. Later, a phase 3 study was conducted comparing DEX-BUP 45 mg/105 mg with placebo in patients with moderate-to-severe MDD. Similarly, MADRS and CGI-S scores were significantly reduced in the treatment group. Adverse effects were similar in all groups. Clinical response to first line treatment options for MDD are reported to be 40%-60%. Availability of additional treatment options, particularly those with reduced time to efficacy, may improve overall treatment and patient quality of life. DEX-BUP is a combination option that has been shown to improve depression symptoms as early as 1 week after initiation.

An increase in urinary primaquine and a reduction in urinary primaquine-5,6-orthoquinone in the Thai population with CYP2D6 reduced enzyme function

ObjectivesPrimaquine is metabolized by the cytochrome P450-2D6 enzyme (CYP2D6) to an active primaquine-5,6-orthoquinone (POQ). No relationships of CYP2D6 polymorphisms with the pharmacokinetics of primaquine and POQ were reported in the Thai population. MethodsWe evaluated the genetic distribution of CYP2D6 in 345 Thai army populations together with the pharmacokinetic profiles of primaquine and POQ in plasma and urine (n = 44, descriptive data are presented in median (range)). All dose-related pharmacokinetic parameters were normalized by primaquine dose per body weight before statistical analysis. ResultsCYP2D6*10 was the allele observed with the highest frequency (56.62%) corresponding to CYP2D6*10/*10 (32.94%) and CYP2D6*1/*10 (27.94%) genotypes. CYP2D6 intermediate metabolizers (CYP2D6 IM) were found in 44.41% of the cohort and had an increase in the cumulative amount of primaquine excreted (CAE) in urine compared to normal metabolizers of CYP2D6 (CYP2D6 NM); (CYP2D6 IM vs. CYP2D6 NM: 2444 (1697–3564) vs. 1757 (1092–2185) μg/mg/kg, p = 0.039), a reduction in urine CAE of POQ (CYP2D6 IM vs CYP2D6 NM: 115 (46–297) vs. 318 (92–498) μg/mg/kg, p = 0.047) and a reduction in the POQ/primaquine CAE ratio in urine (CYP2D6 IM vs. CYP2D6 NM: 0.06 (0.01–0.11) vs. 0.16 (0.06–0.26), p = 0.009). No significant differences were found in the pharmacokinetic profiles of plasma primaquine and POQ. ConclusionsThe CYP2D6 polymorphisms influenced the changes in primaquine and POQ that were noticeable in the urine, supporting the role of the CYP2D6 gene testing before drug administration.

A recent tactic for searching CDK-7 kinase inhibitor by NCI database screening

The present study was based on an exploration of NCI database for searching specific CDK-7 kinase inhibitor by HTVS, SP, XP, molecular dock-ing, molecular dynamic simulation, and ADMET evaluation. The best CDK-7 kinase inhibitors (NCI613391, NCI169676, NCI281246, NCI339580) were identified via NCI database screening. The stability of binding interaction between receptor protein and protein-ligand complex of potent finding com-pounds (NCI613391) was further confirmed by dynamics simulations and MM- -GBSA. The RMSD value of receptor and receptor?ligand complexes was ana-lysed, and it revealed the stability of binding interactions and remained stable throughout the simulation. The RMSF values and gyration radius of the unbound receptor and backbone atoms of the complex were found to be equal, which indicates that the drug molecule inside the CDK7 receptor is also stable. The study of MM-GBSA data also revealed stronger binding interactions of ligands to CDK7 receptors. With the exception of NCI169676, all compounds were shown to be substrates for CYP450 2D6, CYP450 3A4, inhibitors of CYP450 2C9, and non-inhibitors of p-glycoprotein. All compounds were quali-fied and found suitable to be as drug-likeness according to the Lipinski rule, Ghose filter, MDDR like rule and CMC-like rule. The compound (NCI613391) exhibited human intestinal absorption (76.08%), displayed negative AMES and T.E.S.T (US-EPA) toxicity with OSIRIS property and found to be a promising CDK-7 kinase inhibitor and its efficacy may be further explored in clinical trials.

Propafenona Bağlı Gelişen Takotsubo Kardiyomiyopatisi: Sadece Bir Tesadüf mü, Yeni Bir Nedensel İlişki mi?

Propafenone is a class 1C antiarrhythmic drug that blocks sodium channels and is used in the treatment of arrhythmia. Because of its rapid effect on terminating paroxysmal episodes of atrial fibrillation, it can be used as a pill-in-the-pocket. In patients with structural heart disease, it is less preferred due to cardiotoxic effects in long-term use. Although propafenone use is known to cause several cardiovascular side effects, the development of Takotsubo cardiomyopathy is unknown. Propafenone toxicity at standard doses is a rare condition. Propafenone plasma concentrations may increase through inhibition of cytochrome P450 2D6 and complete inhibition of 2D6 metabolism can increase propafenone levels by up to 3 to 10 times. In this case report, we aimed to present a 37-year-old female patient who developed Takotsubo cardiomyopathy and cardiogenic shock after the first dose of propafenone use and recovered with medical treatment.

Impact of CYP2D6 polymorphisms on the efficacy of tamoxifen in Iraqi women with breast cancer

Objectives: The aim of the present study was to investigate the impact of the CYP2D6 genetic polymorphism on clinical outcome in Iraqi breast cancer patients who were candidates for Tamoxifen therapy. Methods: Comprehensive CYP2D6 genotyping was performed in 140 Iraqi women with breast cancer who were women on adjuvant treatment with tamoxifen. Breast cancer patients recruited into the study were divided into two groups: seventy breast cancer women who had no history of recurrence at the time of sampling and had a long time on tamoxifen without recurrence and seventy breast cancer women who had recurrence at the time of sampling after one year of treatment with tamoxifen therapy. Recurrence free survival (RFS) was determined in the recruited patients. Results: Multiple genetic variants of the gene encoding the CYP2D6 enzyme were detected with significant differences in their frequencies and percentages in both recurrent and non-recurrent groups of breast cancer patients. The findings of this study suggest that interindividual variation in clinical outcome may be related to genetic variation in CYP2D6 enzyme, which is characterized by variable RFS periods. Conclusions: This study revealed that the CYP2D6 enzyme of breast cancer patients who participated in this study is highly polymorphic. The CYP2D6 gene of study participants exhibited different allelic combinations with variable frequencies. The multiple genetic variants (alleles) of the gene encoding the CYP2D6 enzyme exhibited significant differences in their frequencies and percentages in both recurrent and non-recurrent groups of breast cancer patients. .The study revealed variable Recurrence free survival (RFS) with highly polymorphic gene. Our study quotes the presence of increased CYP2D6 enzyme polymorphism is associated with variable clinical response.