Cytochrome P450 2C9 Research Articles

CYP2C19 Loss-of-Function is an Associated Risk Factor for Premature Coronary Artery Disease: A Case-Control Study.

Cytochrome P450 2C19 (CYP2C19) is a major enzyme involved in the biotransformation and metabolism of various substances. Loss-of-function of the CYP2C19 gene represents downregulation of CYP2C19 enzyme indication limited or no enzymatic function, which may be, in turn, associated with some disease susceptibility. The relationship between CYP2C19 polymorphisms and susceptibility to premature coronary artery disease (PCAD) is not fully understood. This study aimed to assess this relationship. This study included 635 PCAD patients, and 548 age-matched non-CAD individuals as controls, from November 2019 to August 2023. The CYP2C19 rs4244285 (681G > A, *2) and rs4986893 (636G > A, *3) were genotyped, and the distribution of CYP2C19 polymorphisms between patients and controls and the relationship between CYP2C19 polymorphisms and PCAD risk were analyzed. A total of 442 (37.4%), 543 (45.9%), and 198 (16.7%) individuals had CYP2C19 extensive metabolizer (EM) (*1/*1), intermediate metabolizer (IM) (*1/*2 and *1/*3), and poor metabolizer (PM) (*2/*2, *2/*3, and *3/*3) phenotypes, respectively. CYP2C19 *2/*2 genotype frequency was higher, *1/*1 genotype was lower in PCAD patients than controls. Individuals with CYP2C19 PM phenotype had higher triglyceride (TG) levels than those with CYP2C19 EM or IM phenotypes. Logistic regression analysis showed that body mass index (BMI) ≥24.0 kg/m2 (≥24.0 kg/m2 vs 18.5-23.9 kg/m2, odds ratio (OR): 1.326, 95% confidence interval (CI): 1.041-1.688, p = 0.022), smoking (OR: 1.974, 95% CI: 1.283-3.306, p = 0.002), hypertension (OR: 1.327, 95% CI: 1.044-1.687, p = 0.021), diabetes mellitus (OR: 1.390, 95% CI: 1.054-1.834, p = 0.020), CYP2C19 PM phenotype (PM phenotype vs EM phenotype, OR: 1.701, 95% CI: 1.200-2.411, p = 0.003), and CYP2C19 IM+PM phenotypes (IM+PM vs EM phenotype, OR: 1.369, 95% CI: 1.077-1.740, p = 0.010) were associated with PCAD. CYP2C19 PM or IM+PM phenotypes, overweight, smoking, hypertension, and diabetes mellitus were associated with PCAD.

Candesartan Has No Clinically Meaningful Effect on the Plasma Concentrations of Cytochrome P450 2C8 Substrate Repaglinide in Humans.

In vitro evidence shows that the acyl-β-D-glucuronide metabolite of candesartan inhibits cytochrome P450 (CYP) 2C8 with an inhibition constant of 7.12 μM. We investigated the effect of candesartan on the plasma concentrations and glucose-lowering effect of repaglinide, a sensitive clinical CYP2C8 index substrate. In a randomized crossover study, ten healthy volunteers ingested 8 mg of candesartan or placebo daily for three days, and on day 3, they also ingested 0.25 mg of repaglinide one hour after candesartan or placebo. We measured the plasma concentrations of repaglinide, candesartan, and candesartan acyl-β-D-glucuronide, and blood glucose concentrations for up to nine hours after repaglinide intake. Candesartan had no effect on the area under the plasma concentration-time curve and peak plasma concentration of repaglinide compared with placebo, with ratios of geometric means of 1.02 [P = 0.809; 90% confidence interval (CI) 0.90-1.15] and 1.13 (P = 0.346; 90% CI 0.90-1.43), respectively. Other pharmacokinetic variables and blood glucose concentrations were neither affected. Candesartan acyl-β-D-glucuronide was detectable in seven subjects, in whom the peak concentration of repaglinide was 1.32-fold higher in the candesartan phase than in the placebo phase (P = 0.041; 90% CI 1.07-1.62). Systemic concentrations of candesartan acyl-β-D-glucuronide were very low compared with its CYP2C8 inhibition constant (ratio ≪ 0.1). Furthermore, in a cohort of 93 cancer patients, no indication of decreased paclitaxel clearance was found in four patients using candesartan concomitantly. In conclusion, candesartan therapy is unlikely to inhibit CYP2C8-mediated metabolism of other drugs to any clinically significant extent. SIGNIFICANCE STATEMENT: The findings of this study suggest that candesartan is unlikely to cause drug-drug interactions via inhibition of cytochrome P450 (CYP) 2C8. Although candesartan acyl-β-D-glucuronide has been shown to inhibit CYP2C8 in vitro, it shows no clinically relevant CYP2C8 inhibition in humans due to low systemic concentrations.

Understanding Voriconazole Metabolism: A Middle-Out Physiologically-Based Pharmacokinetic Modelling Framework Integrating In Vitro and Clinical Insights.

Voriconazole (VRC), a broad-spectrum antifungal drug, exhibits nonlinear pharmacokinetics (PK) due to saturable metabolic processes, autoinhibition and metabolite-mediated inhibition on their own formation. VRC PK is also characterised by high inter- and intraindividual variability, primarily associated with cytochrome P450 (CYP)2C19 genetic polymorphism. Additionally, recent in vitro findings indicate that VRC main metabolites, voriconazole N-oxide (NO) and hydroxyvoriconazole (OHVRC), inhibit CYP enzymes responsible for VRC metabolism, adding to its PK variability. This variability poses a significant risk of therapeutic failure or adverse events, which are major challenges in VRC therapy. Understanding the underlying processes and sources of these variabilities is essentialfor safe and effective therapy. This work aimed to develop a whole-body physiologically-based pharmacokinetic (PBPK) modelling framework that elucidates the complex metabolism of VRC and the impact of its metabolites, NO and OHVRC, on the PK of the parent, leveraging both in vitro and in vivo clinical data in a middle-out approach. A coupled parent-metabolite PBPK model for VRC, NO and OHVRC was developed in a stepwise manner using PK-Sim® and MoBi®. Based on available in vitro data, NO formation was assumed to be mediated by CYP2C19, CYP3A4, and CYP2C9, while OHVRC formation was attributed solely to CYP3A4. Both metabolites were assumed to be excreted via renal clearance, with hepatic elimination also considered for NO. Inhibition functions were implemented to describe the complex interaction network of VRC autoinhibition and metabolite-mediated inhibition on each CYP enzyme. Using a combined bottom-up and middle-out approach, incorporating data from multiple clinical studies and existing literature, the model accurately predicted plasma concentration-time profiles across various intravenous dosing regimens in healthy adults, of different CYP2C19 genotype-predicted phenotypes. All (100%) of the predicted area under the concentration-time curve (AUC) and 94% of maximum concentration (Cmax) values of VRC met the 1.25-fold acceptance criterion, with overall absolute average fold errors of 1.12 and 1.14, respectively. Furthermore, all predicted AUC and Cmax values of NO and OHVRC met the twofold acceptance criterion. This comprehensive parent-metabolite PBPK model of VRC quantitatively elucidated the complex metabolism of the drug and emphasised the substantial impact of the primary metabolites on VRC PK. The comprehensive approachcombining bottom-up and middle-out modelling, therebyaccounting for VRC autoinhibition, metabolite-mediated inhibition, and the impact of CYP2C19 genetic polymorphisms, enhances our understanding of VRC PK. Moreover, the model can be pivotal in designing further in vitro experiments, ultimately allowing for extrapolation to paediatric populations, enhance treatment individualisation and improve clinical outcomes.

Limited visibility and uptake of the clopidogrel pharmacogenomic guidelines among cardiologists

Abstract Background Clopidogrel is an antiplatelet agent widely utilised in the treatment of acute coronary syndromes and following coronary interventions. Clopidogrel is a prodrug activated in the liver, mostly by cytochrome P450 2C19 that is encoded by a gene (CYP2C19). Variability in CYPC2C19 affects enzymatic activity and leads to variability in the activation and efficacy of clopidogrel. In 2011, the Clinical Pharmacogenetics Implementation Consortium (CPIC) produced the first set of detailed guidelines on the use of genetic testing to guide the clinical utilization of clopidogrel. Updates on these guidelines were published in 2013 and 2022. However, pre-prescription genetic testing is seldom performed. Purpose To establish whether these pharmacogenomics guidelines have visibility within the cardiovascular (CVD)community and have been incorporated into CVD guidelines. Methods (i) We examine the impact of the CPIC Clopidogrel guidelines released in 2013 and 2022 by looking at the citation patterns in CVD journals indexed in PubMed. (ii) We reviewed the guidelines released by the European Society of Cardiology and the American College of Cardiology on the management of coronary interventions and coronary artery disease over the last 15 years to establish whether CPIC guidelines are making any impact on practice. Results The CPIC 2022 guidelines were cited by 88 articles (49 journals) of which 13 citations (14.7%) appear in CVD journals. None of these citations are in the five major journals in which CVD guideline statements are most frequently published (Nature Review Cardiology, European Heart Journal, Circulation, Journal of the American College of Cardiology, and Journal of the American Medical Association - Cardiology). The 2013 guideline received 366 citations (183 PubMed journals). Of these, 47 were in cardiology journals (12.8%), but only 4 citations were in one of the same five major cardiology journals (2 in Nature Review Cardiology, 1 in Circulation and 1 in JAMA Cardiology). Of the 14 guidelines published by the ESC and ACC over the last 14 years, none cited the CPIC clopidogrel guidelines. Only 6 out of the 14 guidelines mentioned that the efficacy of clopidogrel was modulated by genetic factors but none of them included details or practical implications. Conclusion(s) Whilst sufficient time has not yet elapsed for the 2022 CPIC guidelines to have an impact on the specialist literature, the 2013 guidelines have had limited visibility within the CVD community. Undoubtedly, given the potential contribution of PGx, discussions on its uptakes are ongoing thus far, without resolution. Some considerations of clopidogrel genetics are diffusing into the specialty; however, from the citation evidence, it appears that CPIC clopidogrel guidelines of any vintage have had limited impact in terms of adoption and/or endorsement by cardiologists.

Cannabinoid hyperemesis syndrome: genetic susceptibility to toxic exposure.

Cannabinoid hyperemesis syndrome presents as a complex of symptoms and signs encompassing nausea, vomiting, abdominal pain, and hot water bathing behavior, most typically in a heavy cannabis user. Its presentation is frequently associated with hypothalamic-pituitary-adrenal axis activation with stress and weight loss. Recent investigation has identified five statistically significant mutations in patients distinct from those of frequent cannabis users who lack the symptoms, affecting the TRPV1 receptor, two dopamine genes, the cytochrome P450 2C9 enzyme that metabolizes tetrahydrocannabinol, and the adenosine triphosphate-binding cassette transporter. The syndrome is associated with escalating intake of high potency cannabis, or alternatively, other agonists of the cannabinoid-1 receptor including synthetic cannabinoids. Some patients develop environmental triggers in scents or foods that suggest classical conditioned responses. Various alternative "causes" are addressed and refuted in the text, including exposure to pesticides, neem oil or azadirachtin. Nosological confusion of cannabinoid hyperemesis syndrome has arisen with cyclic vomiting syndrome, whose presentation and pathophysiology are clearly distinct. The possible utilization of non-intoxicating antiemetic cannabis components in cannabis for treatment of cannabinoid hyperemesis syndrome is addressed, along with future research suggestions in relation to its genetic foundation and possible metabolomic signatures.

In silico molecular targets, docking, dynamics simulation and physiologically based pharmacokinetics modeling of oritavancin

IntroductionOritavancin is a semi-synthetic lipoglycopeptide antibiotic primarily used to treat serious infections caused by Gram-positive bacteria. The aim of this study was to elucidate possible molecular targets of oritavancin in human and microbes in relevance to its mechanism of action and model its pharmacokinetics for optimal dose selection in clinical practice.MethodsComputational methods were used in this study which include target prediction, molecular docking, molecular dynamics simulation, pharmacokinetics prediction, and physiological-based pharmacokinetics (PBPK) modeling.ResultsOritavancin was moderately soluble in water and did not permeate the blood-brain barrier. Seven molecular targets were identified in humans. Molecular docking results showed highest binding affinity of oritavancin with PI3-kinase p110-gamma subunit (−10.34 kcal/mol), followed by Acyl-CoA desaturase (−10.07 kcal/mol) and Cytochrome P450 2C19 (−8.384 kcal/mol). Oritavancin PBPK modelling in adult human showed that infusion has lower peak concentrations (Cmax) compared to bolus administration, with 1200 mg dose yielded Cmax of 16.559 mg/L, 800 mg dose yielded Cmax of 11.258 mg/L, and 200 mg over 3 days dose yielded Cmax of 7.526 mg/L. Notably, infusion gave extended half-life (t1/2) for all doses and slightly higher clearance rates compared to bolus, particularly for the 1200 mg and 800 mg doses. The results corroborated existing clinical pharmacokinetic data, and confirmed the model’s accuracy and predictive capability.ConclusionThis comprehensive computational study has provided invaluable insights into the pharmacological profile of Oritavancin, aiding its further development and optimization for clinical use.

CYP2C19 Poor Metabolizer Status and High System Inflammation Response Index are Independent Risk Factors for Premature Myocardial Infarction: A Hospital-Based Retrospective Study.

Atherosclerosis (AS) is a sustained chronic vascular inflammatory response caused by lipid metabolism disorders and immune response disorders and is the main cause of premature (men ≤ 55 years old, women ≤ 65 years old) myocardial infarction (PMI). Cytochrome P450 2C19 (CYP2C19) (related to vascular function and lipid metabolism) and peripheral immune cell levels and plays an important role in the course of AS. The association CYP2C19 polymorphisms, comprehensive immunoinflammatory indices with PMI susceptibility is unclear. This study included 485 PMI patients, and 639 age-matched non-PMI individuals as controls, from January 2019 to March 2024. The relationship between CYP2C19 polymorphisms, peripheral immunoinflammatory indices (pan-immune inflammation value (PIV), systemic immune inflammation index (SII), and system inflammation response index (SIRI)) and PMI risk were analyzed. The inflammatory indices levels in PMI patients were higher than those in controls (all p<0.05). The frequencies of the CYP2C19 *1/*2 and *2/*2 genotypes were higher, while the frequency of the *1/*1 genotype was lower in the PMI patients than those in controls. The cut-off values of TC, TG, LDL-C, PIV, SII, and SIRI were 5.065, 1.305, 2.805, 410.485, 869.645, and 1.495 for distinguishing PMI, respectively. Logistic regression analysis showed that male (odds ratio (OR): 1.607, 95% confidence interval (CI): 1.134-2.277, p=0.008), history of smoking (OR: 7.108, 95% CI: 4.351-11.614, p<0.001), diabetes mellitus (OR: 4.906, 95% CI: 3.333-7.223, p<0.001), CYP2C19 poor metabolizer (PM) (*2/*2, *2/*3, and *3/*3) (OR: 2.147, 95% CI: 1.279-3.603, p=0.004), and high TG (≥1.305 vs <1.305, OR: 2.598, 95% CI: 1.864-3.623, p<0.001) and SIRI level (≥1.495 vs <1.495, OR: 2.495, 95% CI: 1.432-4.349, p=0.001) were independent risk factors for PMI. CYP2C19 PM phenotype, high SIRI level (≥1.495) and TG level (≥1.305), male, history of smoking, and diabetes mellitus were independently associated with PMI susceptibility.

Can CYP2C19 genotyping improve antiplatelet therapy efficacy in real-life practice? Recent advances.

Clopidogrel remains the most widely used P2Y₁₂ receptor inhibitor worldwide and is often used in combination with aspirin for secondary prevention in patients with arterial disease. The drug is associated with a wide response variability with one on three patients exhibiting little or no inhibition of adenosine diphosphate-induced platelet aggregation. It is a prodrug that is mainly metabolized by hepatic cytochrome P450 (CYP) 2C19. Patients who carry a CYP2C19 loss-of-function (LoF) allele have reduced metabolism of clopidogrel that is associated with reduced platelet inhibition compared to non-carriers that is associated with increased risk for thrombotic event occurrences, particularly, stent thrombosis. The United States Food and Drug Administration (US FDA) issued a black box warning in the clopidogrel label highlighting the importance of presence of CYP2C19 LOF allele during the insufficient metabolism of clopidogrel and availability of other potent P2Y₁₂ inhibitor for the treatment in CYP2C19 poor metabolizers. Clinical trials have conclusively demonstrated greater anti-ischemic benefits of prasugrel/ticagrelor in the treatment of patients carrying the CYP2C19 LoF allele. However, uniform use of these more potent P2Y₁₂ inhibitors has been associated with greater bleeding and cost, and lower adherence. The latter information provides a strong rationale for personalizing P2Y₁₂ inhibitor therapy based on the laboratory determination of CYP2C19 genotype. However, cardiologists have been slow to take up pharmacogenetic testing possibly due to lack of provider and patient education, clear cardiology guidelines and, and lack of positive results from adequately sized randomized clinical trials. However, current evidence strongly supports genotyping of patients who are candidates for clopidogrel. Physicians should strongly consider performing genetic tests to identify LoF carriers and treat these patients with more pharmacodynamically predictable P2Y₁₂ inhibitors than clopidogrel.

Study on the cross-resistance of Aedes albopictus (Skuse) (Diptera: Culicidae) to deltamethrin and pyriproxyfen

BackgroundInsecticide resistance poses a significant challenge in the implementation of vector-borne disease control strategies. We have assessed the resistance levels of Aedes albopictus to deltamethrin and pyriproxyfen (PPF) in Fujian Province (China) and investigated the correlation between these resistance levels and mutations in the voltage-gated sodium channel (VGSC).MethodsThe WHO bioassay protocol was used to evaluate the resistance coefficient of Ae. albopictus to deltamethrin and PPF, comparing a susceptible population from the Foshan (FS) area with wild populations from the Sanming (SM), Quanzhou (QZ), Zhangzhou (ZZ), Putian (PT) and Fuzhou (FZ) areas in Fujian Province. Genomic DNA was analyzed by PCR and sequencing to detect knockdown resistance (kdr) in the VGSC, specifically at the pyrethroid resistance alleles V1016V, I1532I and F1534F. Molecular docking was also performed to analyze the binding interactions of PPF and its metabolite 4'-OH-PPF to cytochrome P450 (CYP) 2C19, 2C9 and 3A4 and Ae. albopictus methoprene-tolerant receptors (AeMet), respectively.ResultsThe analysis of resistance to deltamethrin and PPF among Ae. albopictus populations from the various regions revealed that except for the sensitive population in FS and the SM population, the remaining four regional populations demonstrated resistance levels ranging from 4.31- to 18.87-fold for deltamethrin and from 2.85– to 3.62-fold for PPF. Specifically, the FZ and PT populations exhibited high resistance to deltamethrin, whereas the ZZ and QZ populations approached moderate resistance levels. Also, the resistance of the FZ, PT and ZZ populations to PPF increased slowly but consistently with the increasing trend of deltamethrin resistance. Genomic analysis identified multiple non-synonymous mutations within the VGSC gene; the F1534S and F1534L mutations showed significant resistance to deltamethrin in Ae. albopictus. Molecular docking results revealed that PPF and its metabolite 4'-OH-PPF bind to the Ae. albopictus AeMet receptor and CYP2C19.ConclusionsThe wild Ae. albopictus populations of Fujian Province showed varying degrees of resistance to deltamethrin and PPF and a trend of cross-resistance to deltamethrin and PPF. Increased vigilance is needed for potential higher levels of cross-resistance, especially in the PT and FZ regions.Graphical

Age-Dependent Changes in Cytochrome P450 Abundance and Composition in Human Liver.

Cytochrome P450 (CYP) superfamily represents the major drug-metabolizing enzymes responsible for metabolizing over 65% of therapeutic drugs, including those for pediatric use. CYP-ontogeny based physiologically based pharmacokinetic (PBPK) modeling has emerged as useful approach to mechanistically extrapolate adult pharmacokinetic data to children. However, these models integrate physiological differences in the pediatric population including age-dependent differences in the abundances of CYP enzymes. Conventionally, developmental changes in CYP enzymes have been reported using protein abundance and activity data from subcellular fractions such as microsomes, which are prone to high technical variability. Similarly, the available pediatric pharmacokinetic data suffer from the lack of specific CYP substrates, especially in younger children. In the present study, we used viable hepatocytes from 50 pediatric (age, 1 day-18 years) and 8 adult human donors and carried out global proteomics-based quantification of all major hepatic CYP enzymes, including orphan enzymes that have not been studied previously. While CYPs 2B6, 3A5, 4A11, 4F3, and 4V2 did not show a significant association with age, all other quantified isoforms either increased or decreased with age. CYPs 1A2, 2C8, 2C18, and 2C19 were absent or barely detected in the neonatal group, while CYP3A7 was the highest in this group. The >1 to 2 years age group showed the highest total abundance of all CYP enzymes. The age-dependent differences in CYP enzymes reported in this study can be used to develop ontogeny-based PBPK models, which in turn can help improve pediatric dose prediction based on adult dosing, leading to safer drug pharmacology in children. SIGNIFICANCE STATEMENT: We quantified the age-dependent differences in the abundances of hepatic CYP enzymes using a large set of viable pediatric and adult hepatocytes using quantitative global proteomics. We report for the first time the ontogeny in the abundance of CYP enzymes in human hepatocytes, especially, orphan CYPs 20A1, 27A1, 51A1, 7B1, and 8B1 and CYP4 subfamily of enzymes. Our study provides important data about CYP ontogeny that can be used for the better prediction of pediatric pharmacokinetics using physiologically based pharmacokinetic modeling.

Mavacamten for Obstructive Hypertrophic Cardiomyopathy: Rationale for Clinically Guided Dose Titration to Optimize Individual Response.

Mavacamten is the first and only cardiac myosin inhibitor approved in 5 continents for the treatment of adults with symptomatic New York Heart Association class II and III obstructive hypertrophic cardiomyopathy. An evidence-based rationale was used to develop individualized mavacamten dosing, guided by commonly used clinical parameters. Echocardiography is recommended as part of routine clinical assessment of patients with hypertrophic cardiomyopathy, and left ventricular (LV) outflow tract gradient and LV ejection fraction are parameters that can be readily assessed and monitored by echocardiography. Therefore, an echocardiography-based, clinically guided dose-titration strategy was developed to optimize patient benefit from mavacamten for the treatment of symptomatic obstructive hypertrophic cardiomyopathy while minimizing the risk of LV ejection fraction reduction. Results from clinical trials paired with extensive modeling and simulation analyses support a dose-titration and monitoring strategy based on serial echocardiographic measures of Valsalva LV outflow tract gradient and LV ejection fraction. This dosing approach allows for the identification of the lowest individualized mavacamten dose and exposure required to provide improvements in LV outflow tract obstruction, functional capacity, and symptoms. Mavacamten is primarily metabolized by CYP2C19 (cytochrome P450 2C19), and CYP2C19 metabolizer phenotype has an effect on mavacamten exposure. Therefore, this approach has also been demonstrated to provide a favorable safety profile irrespective of patients' CYP2C19 metabolizer status. The dose-titration strategy includes additional considerations for the potential onset of systolic dysfunction in the context of intercurrent illness, and for the potential of drug-drug interactions with inhibitors and substrates of cytochrome P450 enzymes. This posology is reflected in the mavacamten US prescribing information.

Association of Polymorphic Cytochrome P450 Enzyme Pathways with Falls in Multimedicated Older Adults

ObjectivesDose exposure is considered relevant for drug-associated falls in older adults, pointing to an importance of drug metabolism. Aim was to analyze individual factors altering drug metabolism such as enzyme saturation by drug exposure and pharmacogenetics in the context of drug-associated falls. DesignProspective population-based study (ActiFE-Ulm study). Setting and ParticipantsCommunity-dwelling older adults. MethodsFocus was laid on the metabolism by polymorphic cytochrome P450 (CYP) enzymes CYP2C19, 2C9, and 2D6. Relevant variants of pharmacogenes were analyzed. Logistic binary regression analysis was used to calculate odds ratios (ORs) and 95% CIs for falls observed prospectively over a 1-year period with drug metabolism characteristics. ResultsIn total, 1377 participants were included in the analysis. Although the phenotype predicted by the genotype was not, the use of drugs metabolized by CYP2C19 was associated with falls. Drugs not known as fall risk–increasing drugs (FRIDs; ie, non-FRIDs), but metabolized by CYP2C19, showed an OR of 1.46 (1.11-1.93) in adjusted analysis. Significant effect modification was observed for a reduced CYP2C19 activity phenotype with non-FRIDs metabolized by CYP2C19. Conclusions and ImplicationsThis study suggests an association between the occurrence of falls in older adults and the metabolic capacity of CYP2C19. Thus, an important step toward prevention of falls might be to personalize dosage and treatment length of the main drug classes known to be CYP2C19 substrates, such as many antidepressants, opioids, and sedatives, but also proton pump inhibitors in particular in poor and intermediate metabolizers.

Meta-Analysis of Noncompartmental Pharmacokinetic Parameters to Evaluate the Impact of CYP2C19 and CYP2C9 Genetic Polymorphisms on Abrocitinib Exposure.

Abrocitinib is a selective Janus kinase 1 inhibitor approved for the treatment of atopic dermatitis. It is metabolized primarily by cytochrome P450 (CYP) 2C19 (approximately 53%) and CYP2C9 (approximately 30%), which form 2 active metabolites. The pharmacologic activity of abrocitinib is attributable to the unbound exposures of abrocitinib and those metabolites with active moiety area under the plasma concentration-time curve (AUC) considered the best measure of the total pharmacological effect. The effect of CYP2C19 and/or CYP2C9 genotypes on abrocitinib and active moiety exposures were evaluated using a meta-analysis of the noncompartmental estimates of exposure pooled from 10 clinical studies. A linear mixed-effects model was developed on the basis of the power model to evaluate the effect of CYP2C19 and/or CYP2C9 genotypes on exposure (i.e., abrocitinib AUC and peak plasma concentration, active moiety AUC and peak plasma concentration). The genotypes were evaluated individually and as a combined phenotype effect. When evaluating the poor metabolizers of CYP2C19 or CYP2C9 individually, the estimated increases were 44.9% and 42.0% in active moiety AUC, respectively. The combined phenotype models showed a 0.6% decrease, and 25.1% and 10.5% increases in the active moiety AUC for "elevated," "mixed," and "reduced" metabolizers, respectively. Overall, the active moiety exposures did not appear to be affected to a clinically meaningful extent by different genotypes of CYP2C19 and/or CYP2C9.

A factorial-design/assisted HPLC method for simultaneous monitoring of phenytoin, trimethoprim, and sulphamethoxazole in plasma samples to optimize therapy and mitigate toxicity risks

Phenytoin, an anticonvulsant drug, has a narrow therapeutic index and exhibits significant affinity to plasma proteins, mainly albumin. It is mainly metabolized by cytochrome P450 enzymes 2C9, 2C8, and 2C19. The potential for increased phenytoin toxicity may arise when a drug with enzyme-blocking properties are concurrently administered. The co-administration of trimethoprim is reported to decrease phenytoin clearance by 30 %, therefore, monitoring its plasma concentrations is recommended to minimize the risk of its toxicity and optimize its therapeutic efficacy. This study involves development of a novel and simple HPLC method for concurrent measurement of trimethoprim, sulphamethoxazole and phenytoin in plasma samples. The proposed method was optimized using full factorial design to optimize the variable factors affecting chromatographic responses. The separation was performed via isocratic elution on HyperClone C8 column, using a mobile phase consisting of 30: 38.5: 31.5 (v/v/v) of acetonitrile: 3.3 mM heptane-1-sulphonic acid sodium salt: 0.05 M phosphate buffer containing 0.1 % triethylamine at pH 3.7. The mobile phase was delivered at a flow rate of 1 mL/min with UV detection at 210 nm. The method was validated to verify agreement to the criteria set by the International Council for Harmonization (ICH) and Bioanalytical Methods validation. The results showed excellent linearity over the concentration ranges of 0.5–20.0, 1.0–25.0 and 1.0–20.0 µg/mL with detection limits of 0.41, 0.82 and 0.92 µg/mL for trimethoprim, sulphamethoxazole and phenytoin, respectively.The proposed method was extended for the assessment and of the studied drugs in spiked human plasma samples with % recoveries ranging from 92.60 to 105.30 %, indicating bioanalytical applicability. The proposed method can be utilized to study drug-drug interactions for in-patients therapeutic drug monitoring.

In silico investigation of lipid-based compounds implicated in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal, currently incurable neurodegenerative disease that progressively affects the upper motor neurons in the brain and lower motor neurons in the spinal cord. A significant portion of patients exhibit abnormalities in lipid metabolism, which appear to contribute to denervation and subsequent motor neuron degeneration. This study aimed to computationally identify lipid-based compounds associated with ALS and elucidate their pathological and therapeutic roles to facilitate effective ALS diagnosis and treatment. The methodologies employed encompassed rational database searches, pharmacokinetic and target predictions, as well as docking and molecular dynamics simulations (MDS). The findings from the disease-to-lipids analysis identified 20 lipid compounds correlated with ALS, primarily categorized as potential inhibitors within the functional classes of vitamins, antibiotics, organic acids, and phytochemicals. Pharmacokinetic predictions revealed that only four compounds exhibited permeability across the blood&amp;ndash;brain barrier, namely 4-hydroxynonenal, resveratrol, rotenone, and valproic acid. Docking simulations indicated the highest binding affinity for 4-hydroxynonenal with alkaline ceramidase 2 (&amp;minus;4.516 kcal/mol), resveratrol with carbonic anhydrase 6 (&amp;minus;7.070 kcal/mol), rotenone with cytochrome P450 2C19 (&amp;minus;7.378 kcal/mol), and valproic acid with glutamate carboxypeptidase 2 (&amp;minus;5.629 kcal/mol). Furthermore, MDS and molecular mechanics/generalized born surface area calculations demonstrated the stability and binding energies of the complexes under simulated physiological conditions. In summary, further investigation is warranted to explore the synergistic effects of resveratrol and valproic acid in ALS, the mechanisms underlying 4-hydroxynonenal adduct-assisted aggregate formation of certain enzymes in ALS, and the impact of prolonged human exposure to rotenone from marine food sources (such as fish) on the development of ALS.

Formulation and evaluation of dosage form of fast dissolving oral film of Rofecoxib

Rofecoxib is utilized for the treatment of osteoarthritis, rheumatoid joint inflammation, intense torment in grown-ups, and essential dysmenorrhea, just as intense therapy of headache assaults with or without emanations. Rofecoxib is strong. This compound has a place with the stilbenes. These are natural mixes containing a 1,2-diphenylethylene moiety. Stilbenes (C6-C2-C6 ) are acquired from the normal phenylpropene (C6-C3) skeleton building block. The presentation of at least one hydroxyl gathering to a phenyl ring leads to stilbenoids. Rofecoxib has a half-existence of 17 hours and its mean oral bioavailability at restoratively suggested dosages of 125,25,and 50 mg is roughly 93%. The proteins that rofecoxib target incorporate elastin and prostaglandin G/H synthase Cytochrome P4501A2, Cytochrome P4503A4, Cytochrome P4502C9, Cytochrome P4502C8, and Prostaglandin G/H synthase1 are known to processor of Rofecoxib. Rofecoxib oral thin films were prepared from the evaluation studies RCX2 with 98.14% drug release is considered as the optimized formulation.

High Frequency of CYP2C19*3 Heterozygotes Among Patients Under Clopidogrel Treatment in Ouagadougou, Burkina Faso.

&lt;b&gt;Background and Objective:&lt;/b&gt; Despite its widespread use in cardiology, patient's response to clopidogrel exhibits significant interindividual variability, often leading to persistent thromboembolic complications. The hepatic Cytochrome P450 2C19 (CYP2C19) superfamily plays a pivotal role in clopidogrel's conversion to its active form and CYP2C19 polymorphisms significantly contribute to this variability. This study aimed to evaluate the prevalence and impact of the CYP2C19 rs4986893 polymorphism on clopidogrel treatment response. &lt;b&gt;Materials and Methods:&lt;/b&gt; Seventy-three patients with Cardiovascular Diseases (CVD) undergoing clopidogrel antiplatelet therapy for a minimum of six months were recruited from Centre Hospitalier Universitaire Yalgado Ouédraogo (CHU-YO). Sociodemographic data were collected and DNA was extracted from blood samples for CYP2C19 rs4986893 genotyping using PCR-RFLP. &lt;b&gt;Results:&lt;/b&gt; The patient's mean age was 62.56±13.45 years, ranging from 23 to 94 years, with a male-to-female sex ratio of 1.28. Most patients came from the informal sector, primarily of Mossi ethnicity and residing in Ouagadougou. Acute coronary syndromes (ACS) and hypertension were the predominant reasons for consultation, with clopidogrel showing efficacy in 97.3% of cases. While 72.6% had no family history of CVD, hypertension was prevalent among those with familial cardiovascular conditions. Genetic analysis revealed a 65.8% frequency of heterozygotes CYP2C19*1/*3, with no mutant homozygotes CYP2C19*3/*3 detected. The results of the present study underscore a high prevalence of heterozygotes CYP2C19*1/*3 among patients with cardiovascular diseases. &lt;b&gt;Conclusion:&lt;/b&gt; This intermediate metabolic phenotype, along with a good response to clopidogrel, suggests that CYP2C19*1/*3 genotype promotes a favourable response to clopidogrel therapy.

Molecular genomic and epigenomic characteristics related to aspirin and clopidogrel resistance

BackgroundMediators, genomic and epigenomic characteristics involving in metabolism of arachidonic acid by cyclooxygenase (COX) and lipoxygenase (ALOX) and hepatic activation of clopidogrel have been individually suggested as factors associated with resistance against aspirin and clopidogrel. The present multi-center prospective cohort study evaluated whether the mediators, genomic and epigenomic characteristics participating in arachidonic acid metabolism and clopidogrel activation could be factors that improve the prediction of the aspirin and clopidogrel resistance in addition to cardiovascular risks.MethodsWe enrolled 988 patients with transient ischemic attack and ischemic stroke who were evaluated for a recurrence of ischemic stroke to confirm clinical resistance, and measured aspirin (ARU) and P2Y12 reaction units (PRU) using VerifyNow to assess laboratory resistance 12 weeks after aspirin and clopidogrel administration. We investigated whether mediators, genotypes, and promoter methylation of genes involved in COX and ALOX metabolisms and clopidogrel activation could synergistically improve the prediction of ischemic stroke recurrence and the ARU and PRU levels by integrating to the established cardiovascular risk factors.ResultsThe logistic model to predict the recurrence used thromboxane A synthase 1 (TXAS1, rs41708) A/A genotype and ALOX12 promoter methylation as independent variables, and, improved sensitivity of recurrence prediction from 3.4% before to 13.8% after adding the mediators, genomic and epigenomic variables to the cardiovascular risks. The linear model we used to predict the ARU level included leukotriene B4, COX2 (rs20417) C/G and thromboxane A2 receptor (rs1131882) A/A genotypes with the addition of COX1 and ALOX15 promoter methylations as variables. The linear PRU prediction model included G/A and prostaglandin I receptor (rs4987262) G/A genotypes, COX2 and TXAS1 promoter methylation, as well as cytochrome P450 2C19*2 (rs4244285) A/A, G/A, and *3 (rs4986893) A/A genotypes as variables. The linear models for predicting ARU (r = 0.291, R2 = 0.033, p < 0.01) and PRU (r = 0.503, R2 = 0.210, p < 0.001) levels had improved prediction performance after adding the genomic and epigenomic variables to the cardiovascular risks.ConclusionsThis study demonstrates that different mediators, genomic and epigenomic characteristics of arachidonic acid metabolism and clopidogrel activation synergistically improved the prediction of the aspirin and clopidogrel resistance together with the cardiovascular risk factors.Trial registrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT03823274.

CYP2C19 Genotype Is Associated With Adverse Cardiovascular Outcomes in Black Patients Treated With Clopidogrel Undergoing Percutaneous Coronary Intervention.

Cytochrome P450 2C19 (CYP2C19) intermediate and poor metabolizer patients exhibit diminished clopidogrel clinical effectiveness after percutaneous coronary intervention (PCI). However, outcome studies to date have lacked racial diversity. Thus, the impact of CYP2C19 genotype on cardiovascular outcomes in patients treated with clopidogrel who identify as Black or African American remains unclear. Adults among 5 institutions who self-identified as Black or African American, underwent PCI and clinical CYP2C19 genotyping, and were treated with clopidogrel were included. Data were abstracted from health records. Major atherothrombotic (composite of death, myocardial infarction, ischemic stroke, stent thrombosis, or revascularization for unstable angina) and bleeding event rates within 1 year after PCI were compared across CYP2C19 metabolizer groups using multivariable Cox regression adjusted for potential confounders and baseline variables meeting a threshold of P<0.10. The population included 567 Black patients treated with clopidogrel (median age, 62 years; 46% women; 70% with an acute coronary syndrome indication for PCI). Major atherothrombotic events rates were significantly higher among clopidogrel-treated intermediate and poor metabolizers (24 of 125 [19.2%]) versus patients treated with clopidogrel without a no function allele (43 of 442 [9.7%]; 35.1 versus 15.9 events per 100 person-years; adjusted hazard ratio, 2.00 [95% CI, 1.20-3.33], P=0.008). Bleeding event rates were low overall (23 of 567 [4.1%]) and did not differ among the metabolizer groups. Black patients with CYP2C19 intermediate and poor metabolizer phenotypes who are treated with clopidogrel exhibit increased risk of adverse cardiovascular outcomes after PCI in a real-world clinical setting. Bleeding outcomes should be interpreted cautiously. Prospective studies are needed to determine whether genotype-guided use of prasugrel or ticagrelor in intermediate and poor metabolizers improves outcomes in Black patients undergoing PCI.

Clopidogrel resistance and its relevance: Current concepts

ABSTRACT Clopidogrel is the most widely used P2Y12 receptor inhibitor (P2Y12i) as a part of dual antiplatelet therapy along with aspirin. Clopidogrel is a pro-drug and is metabolized to its active metabolite by the hepatic enzyme cytochrome P4502C19 (CYP2C19). This active metabolite is responsible for the antiplatelet action of clopidogrel. Recent studies have demonstrated that single nucleotide polymorphisms in the CYP2C19 gene, including CYP2C19*2,*3,*4, and *5 alleles, result in reduced production of the active metabolite of clopidogrel, and hence reduced inhibition of platelet aggregation. This in turn enhances the incidence of stent thrombosis and recurrent cardiovascular (CV) events. We report a case of coronary stent thrombosis due to clopidogrel resistance proven by CYP2C19 genotyping. We then review the literature on clopidogrel resistance and its impact on CV outcomes. Subsequently, we discuss the methods of diagnosis of resistance, evidence from clinical trials for tailoring clopidogrel therapy, the role of potent P2Y12 inhibitors, the current guidelines, and future directions.