CYP2D6 Enzyme Research Articles

Nonlinear Mixed-Effects Model of Z-Endoxifen Concentrations in Tamoxifen-Treated Patients from the CEPAM Cohort.

Tamoxifen is widely used in patients with hormone receptor-positive breast cancer. The polymorphic enzyme CYP2D6 is primarily responsible for metabolic activation of tamoxifen, resulting in substantial interindividual variability of plasma concentrations of its most important metabolite, Z-endoxifen. The Z-endoxifen concentration thresholds below which tamoxifen treatment is less efficacious have been proposed but not validated, and prospective trials of individualized tamoxifen treatment to achieve Z-endoxifen concentration thresholds are considered infeasible. Therefore, we aim to validate the association between Z-endoxifen concentration and tamoxifen treatment outcomes, and identify a Z-endoxifen concentration threshold of tamoxifen efficacy, using pharmacometric modeling and simulation. As a first step, the CYP2D6 Endoxifen Percentage Activity Model (CEPAM) cohort was created by pooling data from 28 clinical studies (> 7,000 patients) with measured endoxifen plasma concentrations. After cleaning, data from 6,083 patients were used to develop a nonlinear mixed-effect (NLME) model for tamoxifen and Z-endoxifen pharmacokinetics that includes a conversion factor to allow inclusion of studies that measured total endoxifen but not Z-endoxifen. The final parent-metabolite NLME model confirmed the primary role of CYP2D6, and contributions from body weight, CYP2C9 phenotype, and co-medication with CYP2D6 inhibitors, on Z-endoxifen pharmacokinetics. Future work will use the model to simulate Z-endoxifen concentrations in patients receiving single agent tamoxifen treatment within large prospective clinical trials with long-term survival to identify the Z-endoxifen concentration threshold below which tamoxifen is less efficacious. Identification of this concentration threshold would allow personalized tamoxifen treatment to improve outcomes in patients with hormone receptor-positive breast cancer.

Using Negative Control Populations to Assess Unmeasured Confounding and Direct Effects.

Sometimes treatment effects are absent in a subgroup of the population. For example, penicillin has no effect on severe symptoms in individuals infected by resistant Staphylococcus aureus , and codeine has no effect on pain in individuals with certain polymorphisms in the CYP2D6 enzyme. Subgroups where a treatment is ineffective are often called negative control populations or placebo groups. They are leveraged to detect bias in different disciplines. Here we present formal criteria that justify the use of negative control populations to rule out unmeasured confounding and mechanistic (direct) causal effects. We further argue that negative control populations, satisfying our formal conditions, are available in many settings, spanning from clinical studies of infectious diseases to epidemiologic studies of public health interventions. Negative control populations can also be used to rule out placebo effects in unblinded randomized experiments. As a case study, we evaluate the effect of mobile stroke unit dispatches on functional outcomes at discharge in individuals with suspected stroke, using data from a large trial. Our analysis supports the hypothesis that mobile stroke units improve functional outcomes in these individuals.

The Implications of Cytochrome P450 2D6/CYP2D6 Polymorphism in the Therapeutic Response of Atypical Antipsychotics in Adolescents with Psychosis-A Prospective Study.

The plasma level of antipsychotics and their metabolites depends on the activity of the cytochrome P450 (CYP) system in the liver. This research aims to test the individual response variability to atypical antipsychotic drugs, depending on the activity of the CYP2D6 enzyme. In a prospective, noninterventional study, we included 56 adolescents, 51.79% male, diagnosed with schizophrenia. The patients underwent DNA sampling for genotyping SNP by RT-PCR and CYP* allelic variants using Applied Bio-systems™ TaqMan® Assays Foster City, CA, USA). and clinical and paraclinical assessments. The effectiveness of the therapy was evaluated with the PANSS scores at baseline and 3, 6, and 12 months after the initiation of an atypical antipsychotic treatment. Based on the genotyping results, the patients were divided into slow metabolizers (Group 1), extensive metabolizers (Group 2), and intermediate metabolizers (Group 3). The PANSS score showed a significant decrease in Group 2, compared to Group 3 after 3 (p = 0.02), 6 (p = 0.0009), and 12 months (p < 0.0001). The patients in Group 1 showed high PANSS scores, and those in Group 2 had fewer adverse reactions than the other groups. Assessing the CYP2D6 polymorphism may be useful in clinical pediatric psychiatric practice towards improving clinical results and patients' quality of life.

Influence of cytochrome P450 2D6*10/*10 genotype on the risk for tramadol associated adverse effects: a retrospective cohort study.

Background: Tramadol is primarily metabolized by the highly polymorphic CYP2D6 enzyme, leading to a large spectrum of adverse events and clinical response. Ample evidence pointed a reduced CYPD26 activity score in individuals harboring the CYP2D6*10/*10 genotype, nevertheless, there is scarce studies on the impact of CYP2D6*10/*10 genetic polymorphism on long-term tramadol's adverse effects. Aim: To test the correlation between CYP2D6*10/*10 expression and the risk for tramadol-associated adverse effects. Method: Using a database of Leumit Healthcare Services in Israel, we retrospectively assessed the occurrence of adverse events in patients who were prescribed tramadol. A binary logistic regression model was applied to model the relationship between CYP2D6*10/*10 genotype and the occurrence of adverse effects. Results: Data from four hundred ninety-three patients were included in this study. Only 25 (5.1%) patients were heterozygous for the CYP2D6*10 variant, while 56 patients (11%) were tested positive to the CYP2D6*10/*10 genotype. Compared to carriers of other variants, patients with the CYP2D6*10/*10 variant exhibited a higher occurrence of adverse events (odds ratio [OR] = 6.14, 95% confidence interval 3.18-11.83); the odds ratio for central nervous system adverse events and gastrointestinal adverse events were 5.13 (95% CI 2.84-9.28), and 3.25 (95% CI 1.78-5.93), respectively. Conclusion: Among the different CYP2D6 genotypes, CYP2D6*10/*10 genotype carries the higher risk of tramadol related adverse events. Appreciating the frequency of this specific allele it seems prudent to pharmacogenetically screen patients considered for long term tramadol treatment for better tolerability and efficacy outcomes.

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.

THE EFFECT OF CYP2D6 INHIBITORS ON THE THERAPEUTIC EFFICACY OF TAMOXIFENE: LITERATURE REVIEW

INTRODUCTION: Tamoxifen is a selective estrogen receptor modulator and is used to reduce the risk of recurrence of malignant breast cancer, which leads to greater survival in women with this disease. The use of tamoxifen as an adjuvant dramatically decreases the risk of cancer-specific recurrence and mortality. This medication is more accurate than traditional chemotherapies, as there are fewer side effects than other chemotherapeutics. The transformation of tamoxifen initially takes place via hepatic cytochrome P450 into active metabolites. It occurs through the CYP2D6 enzyme, being the main enzyme that participates in the bioactivation of tamoxifen. Endoxifene plasma indices are influenced by the CYP2D6 genotype and the use of drugs that affect CYP2D6 activity. CYP2D6 inhibitors are a broad spectrum of drugs that decrease enzyme activity. OBJECTIVE: The aim of this work is to elucidate, through a literature review, the main drugs that inhibit CYP2D6 and how they influence the therapeutic effect of tamoxifen. METHODS: This present work is a documental, quantitative and literature review research, and for its accomplishment, searches were carried out in electronic databases in Scientific Electronic Library Online (Scielo), MEDLINE, Pubmed, Web Of platforms Science, Science Direct, World Wide Science in a period of six months, using articles that were published during the years 2010 to 2020. RESULTS: The use of drugs that inhibit the CYP2D6 enzyme can be potentially harmful to patients who use tamoxifen in their treatment, causing a decrease in therapeutic efficacy and making it difficult to cure the disease. CONCLUSION: There are several drugs that affect therapeutic efficacy through inhibition of the CYP2D6 enzyme, requiring care and careful observation by health professionals, so that future errors can be avoided. Literature proves that interactions affect the quality of treatment of patients with breast cancer, being able to harm the health of these individuals.

Pharmacological evaluation of a traditional Brazilian medicinal plant, Monteverdia ilicifolia. Part I - Preclinical safety study

Ethnopharmacological relevanceMonteverdia ilicifolia (Maytenus ilicifolia, Celastraceae), known as “espinheira-santa”, has been widely used in Brazil to manage mainly gastrointestinal diseases. This species has been listed in the Brazilian Pharmacopeia and in the National List of Essential Medicines (RENAME). Considering that clinical studies about M. ilicifolia are rare, our group has been performing a broader project designed to evaluate the efficacy of M. ilicifolia capsules in a clinical trial, for this reason, approaches to provide safety to those patients are relevant. Aim of the studyWe aimed to investigate the potential pharmacokinetic interaction and hepatotoxicity and intestinal toxicity of an aqueous extract of M. ilicifolia and its main phytocompounds, catequin, epicatequin, and quercetin. Methods and materialsSlices of liver and intestine of Wistar rats were incubated with different concentrations of M. ilicifolia extract or isolated compounds (catechin, epicatechin and quercetin). Commercial kits were used to evaluate enzyme activities of CYP2D6 and CYP3A4 isoforms, as well as cell viability (MTT) assay and intracellular enzymes leakage, specifically lactate dehydrogenase (LDH), alkaline phosphatase (AP), aspartate aminotransferase (AST), alanine aminotransferase (ALT) were studied. ResultsIncubation with M. ilicifolia extract, catechin, epicatechin and quercetin did not affect significantly any evaluated parameter in intestines. The intracellular enzymes leakages, CYP2D6, LDH and AST, were increased with M. ilicifolia extract and quercetin in liver slices. ConclusionsOur in vitro findings highlighted, for the first time, the potential hepatotoxicity induced by an aqueous extract of M. ilicifolia, consequently this species and its products should be avoided in liver diseases, supporting that studies of safety must be performed including in the context of traditional medicinal plants.

Mechanism-Based Inactivation of CYP2D6 by Phellopterin and Related Drug-Drug Interaction with Metoprolol.

Phellopterin (PLP) is a linear furanocoumarin widely found in citrus fruits and herbal medicines. The study aims to comprehensively investigate the mechanism of inhibition of CYP2D6 enzyme activity by PLP and its alteration of metoprolol pharmacokinetics. PLP was found to irreversibly inhibit CYP2D6 in time-, concentration-, and nicotinamide adenine dinucleotide phosphate-dependent manners. Coincubation with quinidine, which is a competitive inhibitor of CYP2D6, attenuated this time-dependent inhibition. Glutathione (GSH) and catalase/superoxide dismutase failed to reverse the PLP-induced CYP2D6 inactivation. GSH trapping experiments provided strong evidence that PLP metabolic activation produces epoxide or γ-ketoaldehyde intermediates. In addition, pretreatment with PLP resulted in significant increases in Cmax and area under curve of plasma metoprolol in rats.

In Silico Screening of Compounds Similar to Codeine, Tramadol, and Morphine with Better Pharmacodynamic and Pharmacokinetics Profiles

Introduction: Pain alleviation is the primary intervention in promoting quality of life. Among the compounds used in management of pain are opioids. Codeine is mostly used as antitussive and is commonly present in cough syrups. Tramadol and Morphine are used as analgesics based on severity of pain. Although these drugs provide instant pain relief, they are associated with many side effects and the most worrying once are addiction, respiratory depression and tolerance. Methods: Codeine, Tramadol, and Morphine were used as query compounds to generate similar compounds using SwissSimilarity. Similar compounds were docked to mu, kappa, and delta receptors and those that showed better docking scores to mu receptor and lower scores to kappa and delta were analyzed for toxicity profiles using ProTox II and pharmacokinetics profiles using SwissADME. Results: ZINC13831510; 0.992, ZINC03629718; 0. 995; ZINC03870350; 0.993; ZINC28256912; 0.992; and ZINC71774151; 0.977 showed highest binding score to mu receptors and lower to both kappa and delta. All compounds were predicted to inhibit CYP2D6 enzyme. All compounds permeated Blood Brain Barrier with the exceptions of ZINC04102208; 0.992; and ZINC13831510; 0.992. Tramadol, its zinc compounds and ZINC03629718; 0.995. were not substrates for P-glycoprotein. Tramadol and ZINC03639132; 0.976; were predicted immunoactive. All compounds conformed to Lipinski rule of five. Conclusion: In conclusion, ZINC13831510; 0.992; showed the highest binding score to morphine. ZINC02509756; 0.986; and ZINC26259212; 0.995; were considered the safest as compared to Tramadol and Codeine and their zinc compounds respectively. Further invitro studies are recommended for the following promising compounds ZINC13831510; 0.992, ZINC03629718; 0. 995; ZINC03870350; 0.993; ZINC28256912; 0.992; and ZINC71774151; 0.977 ZINC02509756; 0.986; and ZINC26259212; 0.995;.

Predictive bioactivity of compounds from Vitis gracilis leaf extract to counteract doxorubicin-induced cardiotoxicity via sirtuin 1 and adenosine monophosphate-activated protein kinase: An in-silico study

Doxorubicin is a potent chemotherapy drug. However, it is known to cause cardiotoxicity via inhibition of sirtuin 1 (SIRT1) and adenosine monophosphate protein kinase (AMPK) activity in the cardiomyocytes. This research aimed to explore the pharmacokinetics, safety, and bioactivity of compounds from Vitis gracilis leaves in their interaction with SIRT1 and AMPK to counteract doxorubicin-induced cardiotoxicity. A total of 13 selected compounds from V. gracilis leaf extract were screened for their pharmacokinetics, toxicity, and interactions with SIRT1 and AMPK using in silico approach. It was found that the majority of the compounds are easily absorbed by the human intestine, mostly avoiding liver enzyme CYP2D6 interaction and kidney protein OCT2 inhibition. They span nontoxic to harmful, some posing hepatoxic, carcinogenic, and immunotoxic risks, while 12 meet drug-likeness criteria. Finally, molecular docking revealed that several compounds exhibit high binding affinities to the proteins SIRT1 and AMPK, with some even outperforming the standard drug resveratrol such as 3’,4’-dimethoxy-alpha-naphthoflavone, 5-[6-hydroxy-5-(3-methylbut-2-enyl)-1-benzofuran-2-yl]benzene-1,3-diol, 4,4-dimethyl-5alpha-cholesta-8,14,24- trien-3beta-ol, and norethindrone acetate. Therefore, the compounds could be considered candidates of drugs to counteract doxorubicin-induced cardiotoxicity via SIRT1 and AMPK activation.

Formulation and Evaluation of Sublingual Tablets of Meclizine Hydrochloride

The aim of the present research is to formulate sublingual tablet of Meclizine Hydrochloride using direct compression method. Moreover the purpose of developing this dosage form is to provide rapid onset of action beneficial in managing conditions of nausea, vomiting and vertigo, and also overcome the problems of solubility of drug by inclusion complexes. The disease like nausea and vomiting required fast onset of action which is necessary for the fast pharmacological action. So, the sublingual route of administration were better way of medication and overcome the problems like dysphagia. The Meclizine hydrochloride is histamine H1 receptor antagonist with antiemetic and antivertigo properties. The oral bioavailability is low (25%), with low solubility (BCS class 2 drug), and metabolized by Hepatic CYP2D6 enzyme by the process of hepatic hydroxylation. Sublingual tablet of antiemetic drug meclizine hydrochloride will be prepared by direct compression method. The Solubility of sublingual tablets will be enhanced by Inclusion complexes. These are prepared by weighed amount of drug mixed with β-cyclodextrin in different dose ratios [1:1,1:2] was wetted with small drops of water to form kneaded like paste and triturated in mortar pestle for several hours resulting in evaporation of solvent. The inclusion complexes was collected and dried for 48 hours and pulverized using mortar and pestle and then sieved through mesh #60. Then properly mixed with other excipients in polybag for 1 hour. The powder like complex was used for further evaluation studies and to form sublingual tablets by direct compression method.

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.

A software tool to adjust codeine dose based on CYP2D6 gene-pair polymorphisms and drug-drug interactions.

Codeine is metabolized by the CYP2D6 enzyme, and individuals with certain genetic variations of the CYP2D6 gene may metabolize codeine differently, leading to variable efficacy and toxicity. Drug-drug interactions can also affect the metabolism of codeine. A tool to adjust codeine dose based on these factors does not currently exist. Healthcare providers should use their clinical judgment and reference different established dosing guidelines to determine the appropriate dose of codeine for individual patients. The study provides a tool that assists prescribers in adjusting codeine dose based on CYP2D6 gene-pair polymorphisms and drug-drug interactions. Highlighted is the need to consider pharmacogenetics and drug-drug interactions when determining the appropriate dosing of codeine and provide a framework for implementing individualized dosing based on these factors.

CYP1A2 expression rather than genotype is associated with olanzapine concentration in psychiatric patients

Olanzapine is a commonly prescribed atypical antipsychotic agent for treatment of patients with schizophrenia and bipolar disorders. Previous in vitro studies using human liver microsomes identified CYP1A2 and CYP2D6 enzymes being responsible for CYP-mediated metabolism of olanzapine. The present work focused on the impact of CYP1A2 and CYP2D6 genetic polymorphisms as well as of CYP1A2 metabolizing capacity influenced by non-genetic factors (sex, age, smoking) on olanzapine blood concentration in patients with psychiatric disorders (N = 139). CYP2D6 genotype-based phenotype appeared to have negligible contribution to olanzapine metabolism, whereas a dominant role of CYP1A2 in olanzapine exposure was confirmed. However, CYP1A2 expression rather than CYP1A2 genetic variability was demonstrated to be associated with olanzapine concentration in patients. Significant contribution of − 163C > A (rs762551), the most common SNP (single nucleotide polymorphism) in CYP1A2 gene, to enhanced inducibility was confirmed by an increase in CYP1A2 mRNA expression in smokers carrying − 163A, and smoking was found to have appreciable impact on olanzapine concentration normalized by the dose/bodyweight. Furthermore, patients’ olanzapine exposure was in strong association with CYP1A2 expression; therefore, assaying CYP1A2 mRNA level in leukocytes can be an appropriate tool for the estimation of patients’ olanzapine metabolizing capacity and may be relevant in optimizing olanzapine dosage.

Генотипы CYP2D6*3, *4, *6 и гипертрофия эндометрия у больных раком молочной железы на фоне терапии тамоксифеном

Tamoxifen therapy results in endometrial thickening in some patients with hormone-sensitive breast cancer (HSBC). The data on the impact of polymorphic variants of the CYP2D6 gene encoding the CYP2D6 enzyme of the cytochrome P450 family on the efficacy and safety of treatment with tamoxifen are controversial. A prospective cohort study was aimed to explore the association of CYP2D6*3, *4, *6 polymorphisms with the risk of endometrial thickness during adjuvant tamoxifen therapy for HSBC. A total of 145 patients with resectable HSBC, who received 20 mg of oral tamoxifen per day, were enrolled. The CYP2D6*3, *4, *6 polymorphisms were identified by real-time PCR. Endometrial thickness was measured by ultrasonography after 3, 6 and 9 months of endocrine therapy. The study showed that endometrial hyportrophy was more often found in patients having no alternative alleles after 3 months of follow-up (40% against 23.2% in the group of “poor” metabolizers; p = 0.034). Meta-analysis of all follow-up periods has revealed that “normal” metabolizers show a significantly higher rate of endometrial thickness than “poor” metabolizers (OR = 1.88; 95% CI = 1.27–2.79; p = 0.002). A lack of significant differences in indicators of the state of endometrium between groups of patients with different CYD2D6 genotypes and menopausal status requires further investigation.

B-337 Case Report: Fatal Opioid Overdose Induced by Over-the-Counter Cold Medication Diphenhydramine

Abstract Background Accidental drug-related deaths frequently arise following ingestion of multiple co-intoxicants, including opioid analgesics. Hydrocodone, the most prescribed opioid for pain management, is metabolized by hepatic enzymes CYP2D6 and CYP3A4 to the pharmacologically active metabolite hydromorphone and the inactive metabolite norhydrocodone, respectively. As a result, inhibition of CYP2D6 by other pharmacologic agents can impair the analgesic properties of hydrocodone and prolong its half-life in circulation. One such example is diphenhydramine, which is a potent inhibitor of CYP2D6 activity. This case highlights a drug-drug interaction likely resulting in an accidental fatal opioid overdose. Case Presentation A 58-year-old female had longstanding prescriptions for hydrocodone/acetaminophen (Norco® 10/325), alprazolam, carisoprodol, and diltiazem. The decedent had recently taken an over-the-counter cold medication, diphenhydramine (Benadryl), shortly preceding death. A toxicology report (NMS labs, Horsham, PA) from a post-mortem femoral blood sample detected the presence of the following therapeutic compounds by High Performance Liquid Chromatography/Time of Flight-Mass Spectrometry (LC/TOF-MS) analysis: acetaminophen (14 μg/mL), hydrocodone (410 ng/mL), dihydrocodeine (hydrocodol, 24 ng/mL), alprazolam (42 ng/mL), carisoprodol (88 ng/mL), diltiazem (110 ng/mL), and diphenhydramine (150 ng/mL). Hydromorphone, the active metabolite of hydrocodone, was not detected (&amp;lt;2 ng/mL). With the exception of hydrocodone, which was present at fatal concentrations, all other compounds were within therapeutic range. Together, these observations are strongly suggestive of a drug-drug interaction leading to impaired hydrocodone metabolism. Conclusions This case report highlights a fatal opioid overdose as a result of CYP2D6 inhibition by diphenhydramine, a readily available over-the-counter medication. Post-mortem toxicological analysis revealed hydrocodone was present in lethal concentrations, whereas its pharmacologically active metabolite, hydromorphone, was undetectable at time of autopsy. Further, the patient was prescribed a formulation of hydrocodone in combination with acetaminophen, which was present at therapeutic concentrations despite the two drugs having similar elimination half-lives. These toxicological findings suggest administration of diphenhydramine precipitated a deadly accumulation of hydrocodone in the deceased. Overall, this case report underscores the importance of understanding and preventing harmful drug-drug interactions in patients taking opioid medications for pain management.

Comparative metabolism of fargesin in human, dog, monkey, mouse, and rat hepatocytes.

Fargesin, a bioactive lignan derived from Flos Magnoliae, possesses anti-inflammatory, anti-oxidative, anti-melanogenic, and anti-apoptotic effects. This study compared the metabolic profiles of fargesin in human, dog, monkey, mouse, and rat hepatocytes using liquid chromatography-high resolution mass spectrometry. In addition, we investigated the human cytochrome P450 (CYP), UDP-glucuronosyltransferase (UGT), and sulfotransferase (SULT) enzymes responsible for fargesin metabolism. The hepatic extraction ratio of fargesin among the five species ranged from 0.59 to 0.78, suggesting that it undergoes a moderate-to-extensive degree of hepatic metabolism. During metabolism, fargesin generates three phase 1 metabolites, including fargesin catechol (M1) and O-desmethylfargesin (M2 and M3), and 11 phase 2 metabolites, including O-methyl-M1 (M4 and M5) via catechol O-methyltransferase (COMT), glucuronides of M1, M2, M4, and M5, and sulfates of M1-M5. The production of M1 from fargesin via O-demethylenation is catalyzed by CYP2C9, CYP3A4, CYP2C19, and CYP2C8 enzymes, whereas the formation of M2 and M3 (O-desmethylfargesin) is catalyzed by CYP2C9, CYP2B6, CYP2C19, CYP3A4, CYP1A2, and CYP2D6 enzymes. M4 is metabolized to M4 glucuronide by UGT1A3, UGT1A8, UGT1A10, UGT2B15, and UGT2B17 enzymes, whereas M4 sulfate is generated by multiple SULT enzymes. Fargesin is extensively metabolized in human hepatocytes by CYP, COMT, UGT, and SULT enzymes. These findings help to elucidate the pharmacokinetics and drug interactions of fargesin.

Identification of the effects of pathogenic genetic variations of human CYP2C9 and CYP2D6: an in silico approach

Genetic variations in the human cytochrome P450 family 2 subfamily C member 9 (CYP2C9) and cytochrome P450 family 2 subfamily D member 6 (CYP2D6) genes may affect drug metabolism and lead to alterations in phenotypes. Genetic variations are associated with toxicity, adverse drug reactions, inefficient treatment. Various in silico tools were combined to investigate the deleterious effects of missense non-synonymous single nucleotide polymorphisms (nsSNPs) of the human CYP2C9 and CYP2D6. The structural and functional effects of the high-risk non-synonymous SNPs in the human CYP2C9 and CYP2D6 were predicted by numerous computational mutation analysis methods. Out of 24 pathogenic missense SNPs in the CYP2C9, 22 nsSNPs had a decreasing effect on protein stability and 13 SNPs were showed to be located at conserved positions. Out of 27 high-risk deleterious non-synonymous SNPs in the human CYP2D6, 21 SNPs decreased protein stability and 16 nsSNPs were predicted to be positioned at conserved regions. Our present study suggests that the identified functional SNPs may affect drug metabolism associated with CYP2C9 and CYP2D6 enzymes.

Effects of CYP2D6 allelic variants on therapy with tamsulosin in patients with benign prostatic hyperplasia.

Tamsulosin is a first-line drug for the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Despite its high ratings for efficacy and safety, these parameters may vary due togenetic polymorphisms of CYP2D6 enzyme, which is involved in the metabolism of the drug. This variability may have great impact on the therapy of LUTS associated with BPH and may require an individualized approach to drug selection. The aim of the study was to assess the impact of genetic polymorphisms in CYP2D6 on the efficacy and safety of tamsulosin therapy in patients with LUTS associated with BPH. The study included 106 patients with LUTS/BPH (N40 according to ICD-10). All patients received monotherapy with tamsulosin 0.4 mg/day for at least 8weeks. Depending on the severity of symptoms, all patients were divided into 2 groups based on the IPSS score: the first group of patients had moderate symptoms (n=57), and the second group of patients had severe symptoms (n=49). The results of treatment were assessed using the IPSS questionnaire with determination of quality of life (QoL), transrectal ultrasound of the prostate with determination of prostate volume andpostvoid residual urine volume, and uroflowmetry. The carriage of allelic variants of CYP2D6 (*3, *4, *9, *10, and *41) were determined by polymerase chain reaction in all patients. In patients with moderate symptoms who was classified as «intermediate» metabolizers by CYP2D6, a statistically significant greater reduction in symptoms according to the overall IPSS scale at 8weeks (p=0.046) and the obstructive symptom subscale starting from 4weeks of treatment (p<0.05) was shown. Allelic variants of the CYP2D6 gene did not affect the frequency of adverse reactions to tamsulosin. The results of the study show that in patients with moderate LUTS associated with BPH who are «intermediate» metabolizers by CYP2D6, there is a better therapeutic effect of tamsulosin.

Pharmacogenetics of Long-Term Outcomes of Schizophrenia Spectrum Disorders: The Functional Role of CYP2D6 and CYP2C19.

Schizophrenia spectrum disorders (SSD) are complex mental disorders, and while treatment with antipsychotics is important, many patients do not respond or develop serious side effects. Genetic variation has been shown to play a considerable role in determining an individual's response to antipsychotic medication. However, previous pharmacogenetic (PGx) studies have been limited by small sample sizes, lack of consensus regarding relevant genetic variants, and cross-sectional designs. The current study aimed to investigate the association between PGx variants and long-term clinical outcomes in 691 patients of European ancestry with SSD. Using evidence from the literature on candidate genes involved in antipsychotic pharmacodynamics, we created a polygenic risk score (PRS) to investigate its association with clinical outcomes. We also created PRS using core variants of psychotropic drug metabolism enzymes CYP2D6 and CYP2C19. Furthermore, the CYP2D6 and CYP2C19 functional activity scores were calculated to determine the relationship between metabolism and clinical outcomes. We found no association for PGx PRSs and clinical outcomes; however, an association was found with CYP2D6 activity scores by the traditional method. Higher CYP2D6 metabolism was associated with high positive and high cognitive impairment groups relative to low symptom severity groups. These findings highlight the need to test PGx efficacy with different symptom domains. More evidence is needed before pharmacogenetic variation can contribute to personalized treatment plans.