Cytochrome P450 2C9 Research Articles

Abstract 15688: Association of Cytochrome P450 2C19 Polymorphism With Ischemic and Bleeding Risk in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention

Introduction: CYP2C19 isoenzymes of cytochrome P450 impact the effect of clopidogrel. Guidelines recommend clopidogrel in addition to oral anticoagulation (OAC) in patients with atrial fibrillation (AF) after percutaneous coronary intervention (PCI). This study aimed to evaluate the association of CYP2C19 polymorphism with ischemic and bleeding risk in patients with AF undergoing PCI. Methods: Patients with AF and an indication for OAC were included in this two-center prospective cohort study up to 3 days after PCI. Carriers of ≥1 loss of function (LOF) allele CYP2C19*2 were classified as poor metabolisers (PM). Carriers of ≥1 gain of function allele (GOF) were defined as rapid metabolisers (RM). Normal metabolisers (NM) were defined as absence of LOF and GOF alleles. Primary outcome was defined as death, myocardial infarction, or stroke (MACE) at 6 months ±2 weeks. Secondary outcome was defined as non-major clinically relevant (NMCR) or major bleedings. Results: 283 patients were included in the study. Median age was 78 (interquartile range, IQR 72-82) years old and 204 (72%) were males. All patients received treatment with clopidogrel and OAC. 73 (26%) were PM, 108 (38%) were NM and 102 (36%) RM. The primary ischemic outcome occurred in 22 (8%) and the secondary outcome in 38 (13%) patients. PM status did not significantly associate with primary ischemic outcome (PM: 6 [8.2%] vs. NM+RM: 16 [7.6%]; odds ratio, OR 1.09 [95% confidence interval 0.41-2.89], p=0.805). RM status did not significantly associate with bleeding (RM: 14 [13.7%] vs. PM+NM: 24 [13.3%]; OR 1.04 [0.51-2.12], p=1.00). Bleeding rates tended to be lower for patients with PM status (major, NMCR, or minor bleeding: PM 12 [28.7%] vs. NM+RM 84 [40.0%]; 0.61 [0.34-1.07], p=0.09). Conclusions: This pilot study of patients with oral anticoagulation for atrial fibrillation and clopidogrel after PCI ruled out, with 95% confidence, a ≥3-fold increase of ischemic risk for carriers of ≥1 loss of function allele CYP2C19*2 compared with non-carriers. This study was underpowered to detect less pronounced associations. LOF-carrier status might protect from bleeding.

Validating the Prognostic Utility of the ABCD-GENE Score in Asian Patients with Acute Coronary Syndrome Patients on Clopidogrel.

The ABCD-GENE score, which links cytochrome P450 2C19 (CYP2C19) phenotype and high platelet reactivity (HPR) to the risk of major adverse cardiovascular events (MACE) in clopidogrel users, has been validated in white and Japanese populations. The prognostic implications of the score in other Asian cohorts, however, have been largely unchartered. The aim of this study was to validate the prognostic utility of the ABCD-GENE score in a heterogeneous Asian acute coronary syndrome (ACS) cohort. In this single-centre, retrospective cohort evaluation of 423 ACS patients, the objectives were to characterise the best cut-off score for MACE prognostication by comparing the adjusted 1-year risk of MACE between groups above and below the candidate cut-off scores using Cox regression; and for on-clopidogrel HPR prediction using receiver operating characteristic (ROC) analysis and Youden's index. In the adjusted Cox model, an ABCD-GENE score cut-off at 10 points significantly predicts the 1-year risk of MACE (adjusted HR 3.771; 95% CI [1.041-13.661]). Female sex, baseline LDL, history of ACS and angiotensin receptor blocker use were additional independent predictors of MACE. On ROC analysis the ideal cut-off for HPR prediction was 7 points. However, that did not independently predict the 1-year risk of MACE (adjusted HR 1.595; 95% CI [0.425-5.989]). The original ABCD-GENE score 10-point cut-off moderately predicts MACE in a heterogeneous, Asian ACS population at 1 year. Additional predictors of MACE were also identified in the present cohort, and these findings should be prospectively validated in larger ACS cohorts.

The role of CYP2C9 gene polymorphism in rheumatoid arthritis

Background/Aim: The inflammatory disorder rheumatoid arthritis (RA) affects quality of life and worsens with symptoms in the extra-articular tissues and systemic joints. The most significant member of the Cytochrome P450 enzyme family, Cytochrome P450 2C9 (CYP2C9), plays an essential role in the alkylation, demethylation, and hydroxylation of a variety of substances. Insufficient studies as to whether the susceptibility to rheumatoid arthritis is genetic exists. Therefore, our study presents new information on whether CYPC9 is a genetic risk factor. In this study, we sought to determine whether rheumatoid arthritis and the CYP2C9 gene polymorphism are related. Methods: This study was conducted as a prospective case-control study. Fifty patients with RA and 50 healthy individuals were included in our study group. Blood from the controls and patients was drawn into ethylenediaminetetraacetic acid (EDTA)-containing tubes, and using a DNA isolation kit, DNA was isolated from leukocytes. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to assess the genotypes of CYPC9*2 and CYP2C9*3 with the LightCycler-CYP2C9 mutation detection kit. Results: The heterozygous CYP2C9*2 genotype was found to carry a 2.85-fold risk when compared with the controls (odds ratio [OR]=2.85, 95% confidence interval [CI]: 0.52–15.50; P=0.22); however, this risk was not statistically significant. It was found that people with the CYP2C9*3 heterozygous genotype had a statistically significant 2.79-fold higher risk compared to the controls (OR=2.79, 95% CI: 1.13–7.00 P=0.04). Conclusion: The heterozygous genotype of CYP2C9*3 may contribute to the onset of RA.

Metabolism of testosterone and progesterone by cytochrome P450 2C19 allelic variants.

CYP2C19 is a member of the human microsomal cytochrome P450 (CYP). Significant variation in CYP2C19 levels and activity can be attributed to polymorphisms in this gene. Wildtype CYP2C19 and 13 mutants (CYP2C19.1B, CYP2C19.5A, CYP2C19.5B, CYP2C19.6, CYP2C19.8, CYP2C19.9, CYP2C19.10, CYP2C19.11, CYP2C19.13, CYP2C19.16, CYP2C19.19, CYP2C19.23, CYP2C19.30, and CYP2C19.33) were coexpressed with NADPH-cytochrome P450 reductase in Escherichia coli. Hydroxylase activity toward testosterone and progesterone was also examined. Ten CYP2C19 variants showed Soret peaks (450nm) typical of P450 in the reduced CO-difference spectra. CYP2C19.11 and CYP2C19.23 showed higher testosterone 11α, 16α-/17- and progesterone 6β-,21-,16α-/17α-hydroxylase activities than CYP2C19.1B. CYP2C19.6, CYP2C19.16, CYP2C19.19, and CYP2C19.30 showed lower activity than CYP2C19.1B. CYP2C19.9, CYP2C19.10. CYP2C19.13, and CYP2C19.33 showed different hydroxylation activities than CYP2C19.1B. These results indicated that CYP2C19 variants have very different substrate specificities for testosterone and progesterone.

The involvement of hepatic cytochrome P450s in the cytotoxicity of lapatinib.

Lapatinib, an oral tyrosine kinase inhibitor used as a first-line treatment for HER2-positive breast cancer, has been reported to be associated with hepatotoxicity; however, the underlying mechanisms remain unclear. In this study, we report that lapatinib causes cytotoxicity in multiple types of hepatic cells, including primary human hepatocytes, HepaRG cells, and HepG2 cells. A 24-h treatment with lapatinib induced cell cycle disturbances, apoptosis, and DNA damage, and decreased the protein levels of topoisomerase in HepG2 cells. We investigated the role of cytochrome P450 (CYP)-mediated metabolism in lapatinib-induced cytotoxicity using our previously established HepG2 cell lines, which express each of 14 CYPs (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, and 3A7). We demonstrate that lapatinib is metabolized by CYP1A1, 3A4, 3A5, and 3A7. Among these, lapatinib-induced cytotoxicity and DNA damage were attenuated in cells overexpressing CYP3A5 or 3A7. Additionally, we measured the production of three primary metabolites of lapatinib (O-dealkylated lapatinib, N-dealkylated lapatinib, and N-hydroxy lapatinib) in CYP1A1-, 3A4-, 3A5-, and 3A7-overexpressing HepG2 cells. We compared the cytotoxicity of lapatinib and its 3 metabolites in primary human hepatocytes, HepaRG cells, and HepG2 cells and demonstrated that N-dealkylated lapatinib is more toxic than the parent drug and the other metabolites. Taken together, our results indicate that lapatinib-induced cytotoxicity involves multiple mechanisms, such as apoptosis and DNA damage; that N-dealkylated lapatinib is a toxic metabolite contributing to the toxic effect of lapatinib; and that CYP3A5- and 3A7-mediated metabolism plays a role in attenuating the cytotoxicity of lapatinib.

Effect of nivasorexant (ACT-539313), a selective orexin-1-receptor antagonist, on multiple cytochrome P450probe substrates in vitro and in vivo using a cocktail approach in healthy subjects.

Nivasorexant, a selective orexin-1-receptor antagonist, has recently been assessed in the treatment of humans with binge-eating disorder. Herein, the inhibitory potential of nivasorexant on cytochromes P450 (CYPs) 2C9, 2C19, and 3A4 was evaluated. Human liver microsomes/recombinant CYP enzymes were evaluated in vitro. In vivo, a single-center, open-label, fixed-sequence study was performed in healthy adults to explore the effect of 100 mg nivasorexant administered twice daily (b.i.d.) on the pharmacokinetics (PK) of flurbiprofen (50 mg, CYP2C9), omeprazole (20 mg, CYP2C19), midazolam (2 mg, CYP3A4) making use of a cocktail approach. Plasma PK sampling was performed over 24 h on Day 1 (Cocktail alone), 8 (Cocktail + nivasorexant), and 15 (Cocktail + nivasorexant at steady state). Genotyping of subjects' CYPs was performed while safety and tolerability were also assessed. In vitro, nivasorexant inhibited CYP2C9, 2C19, and 3A4 in competitive inhibition assays with IC50 values of 8.6, 1.6, and 19-44 μM, respectively, while showing a significant time-dependent CYP2C19 inhibition. In 22 subjects, exposure to flurbiprofen, omeprazole, and midazolam was generally higher during concomitant single- (i.e., area under the plasma concentration-time curve [AUC] ratio increased by 1.04-, 2.05-, and 1.56-fold, respectively) and repeated-dose (i.e., AUC ratio increased by 1.47-, 6.84-, and 3.71-fold, respectively) nivasorexant administration compared with the cocktail substrates administered alone. The most frequently reported adverse event was somnolence. According to regulatory guidance, nivasorexant is classified as a moderate CYP2C19 and weak CYP3A4 inhibitor after 1 day and as a weak CYP2C9, strong CYP2C19, and moderate CYP3A4 inhibitor after 8 days of 100 mg b.i.d. administration. Clinicaltrials.gov ID: NCT05254548.

Scutellarin Mediates Cytochrome P450 3A4 and 2C19 Expression via Pregnane X Receptor and Constitutive Androstane Receptor.

Breviscapine is a flavonoid extracted from Erigeron breviscapus (Vant.) Hand.-Mazz., and mainly contains scutellarin. Nuclear receptors play important roles in regulating transporter and drug metabolic enzymes. To investigate the regulatory effects of scutellarin on CYP3A4 and 2C19 in HepG2 and Caco-2 cells based on nuclear receptors PXR and CAR. The proteins and mRNA levels of CYP3A4 and CYP2C19 treated with scutellarin were detected by Western Blot and RT-qPCR. Using assays of the dual-luciferase reporter, promoter sequences containing hPXR and hCAR protein recognition and binding regulatory elements CYP3A4 and CYP2C19 were inserted upstream of the reporter gene, and the expression vector and the reporter vector were cotransfected into HepG2 and Caco-2 cells. Scutellarin inhibited mRNA of CYP3A4 and PXR, and promoted mRNA expression of CYP2C19 and CAR in RT-qPCR results. Western-blot results showed scutellarin inhibited the expression of CYP3A4 and promoted the expression of CYP2C19. The dual-luciferase reporter genes showed that scutellarin enhanced the expression level of CYP2C19, and when its concentration was 40 and 80μmol/L, CYP3A4 was significantly increased. Scutellarin down-regulates CYP3A4 through PXR, and its mechanism may work by up-regulating CAR, binding to PXR to inhibit PXR-mediated expression of CYP3A4. Scutellarin up-regulates CYP2C19 through CAR.

Determining the CYP2C19*2 and CYP2C19*3 polymorphisms among patients with gastroduodenal diseases by PCR-RFLP technique

Background: Pharmacogenetics is at the heart of precision medicine. The CYP2C19 gene encodes the cytochrome P450 2C19 enzyme which is involved in the metabolism of proton pumps inhibitors in liver. The most common alelles encoding non-functional proteins are CYP2C19*2 and CYP2C19*3. Objectives: (1) Establish a process to identify CYP2C19*2 and *3 polymorphisms by PCR-RFLP technique; (2) Determine the prevalence of CYP2C19 genotypes by *2 and *3 polymorphisms among H. pylori-positive patients with gastroduodenal diseases. Materials and methods: DNA samples were extracted from 112 gastric biopsy specimens. The CYP2C19*2 and *3 polymorphisms were identified by PCR-RFLP technique. Confirming the results in 10% of the samples randomly by Sanger sequencing. Results: The PCR-RFLP results of validated samples were in 100% concordance with sequencing results. The frequencies of the *1, *2 and *3 alleles of the CYP2C19 gene were 67.9%, 29% and 3.1%, respectively. The proportion of groups with normal metabolizer, intermediate metabolizer and poor metabolizer genotypes were 45.5%, 44.7% and 9.8%, respectively. Conclusion: The intermediate/poor metabolizer genotype accounted for a high rate. PCR-RFLP is an accurate and cost-effective method to determine CYP2C19*2 and CYP2C19*3 polymorphisms. This technique can be applied to identify polymorphisms in patients with gastroduodenal disorders as a guidance for personalized therapy. Key words: CYP2C19*2, CYP2C19*3, PCR-RFLP, gastroduodenal diseases, pharmacogenetics.

High Platelet Reactivity Combined with CYP2C19 Genotype in Predicting Outcomes in East Asian Patients Undergoing Percutaneous Coronary Intervention.

Loss-of-function (LoF) alleles of cytochrome P450 2C19 (CYP2C19), which are prevalent in East Asians, are linked to high platelet reactivity (HPR) phenotype and poor prognosis. We aimed to investigate the incremental predictive value of HPR combined with CYP2C19 genotype in predicting outcomes after drug-eluting stent (DES) implantation. The patients treated with platelet function and genotype-related long-term prognosis in drug-eluting stent (PTRG-DES) consortium enrolled a total of 13,160 Korean patients treated with DES who had platelet function test (PFT) or CYP2C19 genotype, of which, 6,717 patients with PFT and genotype together were categorized. HPR was defined as VerifyNow ≥ 252 P2Y12 reaction unit. The primary outcome was the incidence of major adverse cardiac and cerebrovascular event (MACCE) 5 years after treatment. The patients with both HPR and CYP2C19 LoF/LoF had the highest MACCE rates (6.2%) and increased MACCE risk (adjusted hazard ratio: 1.89, 95% confidence interval: 1.20-2.91, P = 0.006) compared with those without both HPR and CYP2C19 LoF/LoF. There was no effect of interaction between HPR and CYP2C19 genotype on the primary outcome (P = 0.424). Adding combined HPR and CYP2C19 genotype to the conventional model had an incremental influence in predicting MACCE and stent thrombosis. Compared to the model including HPR or CYP2C19 genotype alone, a combination model significantly improved the risk stratification for stent thrombosis but not MACCE. In DES-treated East Asian patients, the combined evaluation of PFT results and CYP2C19 genotyping might improve risk prediction of ischemic events during clopidogrel treatment.

The impact of gene polymorphism and hepatic insufficiency on voriconazole dose adjustment in invasive fungal infection individuals.

Voriconazole (VRZ) is a broad-spectrum antifungal medication widely used to treat invasive fungal infections (IFI). The administration dosage and blood concentration of VRZ are influenced by various factors, posing challenges for standardization and individualization of dose adjustments. On the one hand, VRZ is primarily metabolized by the liver, predominantly mediated by the cytochrome P450 (CYP) 2C19 enzyme. The genetic polymorphism of CYP2C19 significantly impacts the blood concentration of VRZ, particularly the trough concentration (Ctrough), thereby influencing the drug's efficacy and potentially causing adverse drug reactions (ADRs). Recent research has demonstrated that pharmacogenomics-based VRZ dose adjustments offer more accurate and individualized treatment strategies for individuals with hepatic insufficiency, with the possibility to enhance therapeutic outcomes and reduce ADRs. On the other hand, the security, pharmacokinetics, and dosing of VRZ in individuals with hepatic insufficiency remain unclear, making it challenging to attain optimal Ctrough in individuals with both hepatic insufficiency and IFI, resulting in suboptimal drug efficacy and severe ADRs. Therefore, when using VRZ to treat IFI, drug dosage adjustment based on individuals' genotypes and hepatic function is necessary. This review summarizes the research progress on the impact of genetic polymorphisms and hepatic insufficiency on VRZ dosage in IFI individuals, compares current international guidelines, elucidates the current application status of VRZ in individuals with hepatic insufficiency, and discusses the influence of CYP2C19, CYP3A4, CYP2C9, and ABCB1 genetic polymorphisms on VRZ dose adjustments and Ctrough at the pharmacogenomic level. Additionally, a comprehensive summary and analysis of existing studies' recommendations on VRZ dose adjustments based on CYP2C19 genetic polymorphisms and hepatic insufficiency are provided, offering a more comprehensive reference for dose selection and adjustments of VRZ in this patient population.

Association of CYP2C9*2 Allele with Sulphonylurea-Induced Hypoglycaemia in Type 2 Diabetes Mellitus Patients: A Pharmacogenetic Study in Pakistani Pashtun Population.

Polymorphism in cytochrome P450 (CYP) 2C9 enzyme is known to cause significant inter-individual differences in drug response and occurrence of adverse drug reactions. Different alleles of the CYP2C9 gene have been identified, but the notable alleles responsible for reduced enzyme activity are CYP2C9*2 and CYP2C9*3. No pharmacogenetic data are available on CYP2C9*2 and CYP2C9*3 alleles in the Pakistani population. In Pakistan, pharmacogenetics, which examines the relationship between genetic factors and drug response, are in the early stages of development. We, for the first time, investigated the association between the CYP2C9 variant alleles CYP2C9*2 and CYP2C9*3 and the incidence of hypoglycaemia in patients with Type 2 diabetes mellitus (T2DM) receiving sulphonylurea medications. A total of n = 400 individuals of Pashtun ethnicity were recruited from 10 different districts of Khyber Pakhtunkhwa, Pakistan to participate in the study. The study participants were divided into two distinct groups: the case group (n = 200) and the control group (n = 200). The case group consisted of individuals with T2DM who were receiving sulphonylurea medications and experienced hypoglycaemia with it, whereas the control group included individuals with T2DM who were receiving sulphonylurea medication but did not experience sulphonylurea-induced hypoglycaemia (SIH). Blood samples were obtained from study participants following informed consent. DNA was isolated from whole blood samples using a Wiz-Prep DNA extraction kit. Following DNA isolation, CYP2C9 alleles were genotyped using MassARRAY sequencing platform at the Centre of Genomics at the Rehman Medical Institute (RMI). The frequency of CYP2C9*2 (low-activity allele) was more frequent in the diabetic patients with SIH compared to the control group (17.5% vs. 6.0%, p = 0.021). The frequency of its corresponding genotype CYP2C9*1/*2 was higher in cases compared to the control group (10% vs. 6% with p = 0.036); the same was true for genotype CYP2C9*2/*2 (7% vs. 3.5% with p = 0.028). Logistic regression analysis evidenced potential association of CYP2C9*2 allele and its genotypes with SIH. When adjusted for confounding factors such as age, weight, sex, mean daily dose of sulphonylurea, and triglyceride level, the association between the CYP2C9*2 allele and hypoglycaemia remained consistent. Confounding factors played no role in SIH (insignificant p-value) because both groups (cases and controls) were closely matched in term of age, weight, sex, mean daily dose of sulphonylurea, and triglyceride levels. Our study suggests that genetic information about a patient's CYP2C9 gene/enzyme can potentially assist physicians in prescribing the most suitable and safest drug, based on their genetic make-up.

Hepatic biotransformation of non-psychotropic phytocannabinoids and activity screening on cytochromes P450 and UDP-glucuronosyltransferases

This study examined the biotransformation of phytocannabinoids in human hepatocytes. The susceptibility of the tested compounds to transformations in hepatocytes exhibited the following hierarchy: cannabinol (CBN) > cannabigerol (CBG) > cannabichromene (CBC) > cannabidiol (CBD). Biotransformation included hydroxylation, oxidation to a carboxylic acid, dehydrogenation, hydrogenation, dehydration, loss/shortening of alkyl, glucuronidation and sulfation. CBN was primarily metabolized by oxidation of a methyl to a carboxylic acid group, while CBD, CBG and CBC were preferentially metabolized by direct glucuronidation. The study also screened for the activity of recombinant human cytochromes P450 (CYPs) and UDP-glucuronosyltransferases (UGTs), which could catalyze the hydroxylation and glucuronidation of the tested compounds, respectively. We found that CBD was hydroxylated mainly by CYPs 2C8, 2C19, 2D6; CBN by 1A2, 2C9, 2C19 and 2D6; and CBG by 2B6, 2C9, 2C19 and 2D6. CBC exhibited higher susceptibility to CYP-mediated transformation than the other tested compounds, mainly with CYPs 1A2, 2B6, 2C8, 2C19, 2D6 and 3A4 being involved. Further, CBD was primarily glucuronidated by UGTs 1A3, 1A7, 1A8, 1A9 and 2B7; CBN by 1A7, 1A8, 1A9 and 2B7; CBG by 1A3, 1A7, 1A8, 1A9, 2B4, 2B7 and 2B17; and the glucuronidation of CBC was catalyzed by UGTs 1A1, 1A8, 1A9 and 2B7.

Frequencies of Combined Dysfunction of Cytochromes P450 2C9, 2C19, and 2D6 in an Italian Cohort: Suggestions for a More Appropriate Medication Prescribing Process.

Improper drug prescription is a main cause of both drug-related harms (inefficacy and toxicity) and ineffective spending and waste of the healthcare system's resources. Nowadays, strategies to support an improved, informed prescription process may benefit from the adequate use of pharmacogenomic testing. Using next-generation sequencing, we analyzed the genomic profile for three major cytochromes P450 (CYP2C9, CYP2C19, CYP2D6) and studied the frequencies of dysfunctional isozymes (e.g., poor, intermediate, or rapid/ultra-rapid metabolizers) in a cohort of 298 Italian subjects. We found just 14.8% of subjects with a fully normal set of cytochromes, whereas 26.5% of subjects had combined cytochrome dysfunction (more than one isozyme involved). As improper drug prescription is more frequent, and more burdening, in polytreated patients, since drug-drug interactions also cause patient harm, we discuss the potential benefits of a more comprehensive PGX testing approach to support informed drug selection in such patients.

Differences in the Proportion of CYP2C19 Loss-of-Function Between Cerebral Infarction and Coronary Artery Disease Patients.

Cytochrome P450 2C19 (CYP2C19) genotypes and metabolic phenotypes (extensive metabolizer (EM), intermediate metabolizer (IM), and poor metabolizer (PM)) are related to the metabolism of therapeutic drugs for cardiovascular and cerebrovascular diseases. This study aimed to investigate the differences of CYP2C19 gene polymorphism distribution between coronary artery disease (CAD) patients and cerebral infarction (CI) patients. We identified 413 CI patients, 509 CAD patients, and 241 CI+CAD patients from 2016 to 2020 and studied genotypes of CYP2C19 rs4986893 (636G>A) and rs4244285 (681G>A) polymorphisms using PCR-gene chip detection method. Differences in CYP2C19 genotypes and metabolic phenotypes between the groups were compared. To analyze the efficacy of CYP2C19 metabolic phenotypes in discriminating between cerebral infarction and coronary artery disease, multiple logistic regression analysis was conducted after adjusting for gender, age, smoking history, drinking history, hypertension, and diabetes. There were significant differences in the distribution of CYP2C19 genotypes and metabolic phenotypes between CI and CAD patients. The results of multivariate logistic regression (adjusted for sex, age, smoking, drinking, hypertension, and diabetes) indicated that CYP2C19 IM phenotype (IM vs EM: OR 1.443, 95% CI: 1.086-1.918, P=0.011) and CYP2C19 IM+PM phenotype (IM or PM vs EM: OR 1.440, 95% CI: 1.100-1.885, P=0.008) may be indicators of CI from CAD. CYP2C19 EM metabolic phenotype was dominant in CAD patients, and CYP2C19 IM metabolic phenotype was dominant in CI patients. After adjusting for other confounding factors, patients with the CYP2C19 IM metabolic phenotype were more likely to develop CI than CAD.

Warfarin and Antibiotics: Drug Interactions and Clinical Considerations.

Warfarin administration poses a notable challenge in clinical practice due to the increased susceptibility of patients to major bleeding, particularly when co-administered with other medications capable of modulating its metabolic pathways. Among these medications, antibiotics have been recognized as potential agents that can either induce or inhibit cytochrome P450-2C9, thereby impacting the effects of warfarin. A wealth of evidence from numerous studies consistently supports an elevated risk of serious bleeding in patients concurrently receiving antibiotics and warfarin therapy. This narrative review elucidates the intricate interactions between warfarin and various antibiotic classes. Notably, significant increases in the International Normalized Ratio (INR) were observed among warfarin-treated patients receiving penicillin derivatives, fluoroquinolones, TMP-SMX, and macrolides. Conversely, investigations have also demonstrated a reduction in INR levels in patients on warfarin when exposed to rifampin, a potent inducer of cytochrome P-450. Intriguingly, cephalosporin antibiotics and amoxicillin/clavulanate, despite not interfering with the cytochrome P450 system, exhibited a positive association with increased INR values. The findings of this narrative review underscore the importance of diligent monitoring in patients on warfarin requiring concomitant antibiotic therapy, as this surveillance strategy proves pivotal in mitigating the risk of major bleeding complications. Additionally, for patients necessitating cytochrome P450 inhibitors such as penicillin derivatives, fluoroquinolones, TMP-SMX, and macrolides, the consideration of dose reduction in warfarin therapy may confer substantial benefits in reducing the occurrence of major bleeding events. Similarly, patients who are co-administered rifampin alongside warfarin necessitate vigilant monitoring, with a potential need for escalating warfarin doses to counteract the risk of a hypercoagulable state.

Therapeutic drug monitoring of voriconazole and CYP2C19 phenotype for dose optimization in paediatric patients.

The objective of this study was to evaluate factors influencing voriconazole (VRC) plasma trough concentrations and provide research data for optimizing VRC dosing in Chinese paediatric patients. Medical records of inpatients were reviewed retrospectively. Multivariate linear regression analysis was used to identify the factors contributing to the variability of VRC plasma trough concentrations. A total of 250 VRC plasma trough concentrations from 131 paediatric patients were included in the analysis. The median VRC plasma trough concentration was 1.28mg·L-1 (range, 0.02 to 9.69mg·L-1). The target range was achieved in 51.6% of patients, while subtherapeutic and supratherapeutic concentrations were obtained in 40.4% and 8.0% of paediatric patients, respectively. The most commonly identified cytochrome P450 2C19 (CYP2C19) phenotype was intermediate metabolizers (IMs) (48.9%), followed by normal metabolizers (NMs) (40.5%) and poor metabolizers (PMs) (10.7%), but no ultrarapid metabolizers (UMs) were observed in our study. VRC plasma trough concentrations adjusted for dose (Cmin/D) were significantly lower in both NMs and IMs compared to PMs (PN-P < 0.001 and PI-P = 0.010, respectively). The dosage of VRC required to achieve the therapeutic range was related to age, with children aged < 6years needing a significantly higher oral dose of VRC. The oral and intravenous maintenance doses needed to reach the therapeutic range were significantly lower than the recommended maintenance dose (P < 0.001, P < 0.001). Factors such as CYP2C19 polymorphisms, the combination of omeprazole, levels of albumin and alanine aminotransferase, were found to affect VRC exposure and explained some of the variability. The VRC plasma trough concentration is significantly influenced by the CYP2C19 phenotype. The recommended maintenance dose for pediatric patients may not be appropriate for Chinese patients. To increase the probability of achieving the therapeutic range for VRC plasma trough concentration, the administration of VRC should consider the age of paediatric patients and the presence of CYP2C19 polymorphisms.

Patient understanding of pharmacogenomic test results in clinical care

ObjectivePrevious research has not objectively assessed patients’ comprehension of their pharmacogenomic test results. In this study we assessed understanding of patients who had undergone cytochrome P450 2C19 (CYP2C19) pharmacogenomic testing. Methods31 semi-structured interviews with patients who underwent CYP2C19 testing after cardiac catheterization and had been sent a brochure, letter, and wallet card explaining their results. Answers to Likert and binary questions were summarized with descriptive statistics. Qualitative data were analyzed using a grounded theory approach, with particular focus on categorization. ResultsNo participants knew the name of the gene tested or their metabolizer status. Seven participants (23%) knew whether the testing identified any medications that would have lower effectiveness or increased adverse effects for them at standard doses (“Adequate Understanding”). Four participants (13%) read their results from the letter or wallet card they received but had no independent understanding (“Reliant on Written Materials”). Ten participants remembered receiving the written materials (32%). ConclusionA majority of participants who had undergone CYP2C19 PGx testing did not understand their results at even a minimal level and would be unable to communicate them to future providers. Practice implicationsFurther research is necessary to improve patient understanding of PGx testing and their results, potentially through improving patient-provider communication.

The relationship between genetic polymorphism of CYP2C19 and the efficacy of Helicobacter pylori eradication therapy in children

Objective: To investigate the relationship between genetic polymorphisms of cytochrome P450 2C19 (CYP2C19) and the efficacy of Helicobacter pylori (Hp) eradication therapy in children. Methods: The retrospective cohort study was conducted on 125 children with gastroscopy and positive rapid urease test (RUT) from September 2016 to December 2018 who presented to the Children's Hospital of Zhejiang University School of Medicine due to gastrointestinal symptoms including nausea, vomiting, abdominal pain, bloating, acid reflux, heartburn, chest pain, vomiting blood and melena. Hp culture and drug susceptibility test were carried out with gastric antrum mucosa before treatment. All the patients completed 2 weeks of standardized Hp eradication therapy and had 13C urea breath test 1 month after that, which was used to evaluate the curative effect. The DNA of gastric mucosa after RUT was analyzed and CYP2C19 gene polymorphism was detected. Children were grouped according to metabolic type. Combined with the results of Hp culture and drug susceptibility, the relationship between CYP2C19 gene polymorphism and the efficacy of Hp eradicative treatment was analyzed in children. Chi square test was used for row and column variables, and Fisher exact test was used for comparison between groups. Results: One hundred and twenty five children were enrolled in the study, of whom 76 were males and 49 females. The genetic polymorphism of CYP2C19 in these children found poor metabolizer (PM) of 30.4% (38/125), intermediate metabolizer (IM) of 20.8% (26/125), normal metabolizer (NM) of 47.2% (59/125), rapid metabolizer (RM) of 1.6% (2/125), and ultrarapid metabolizer (UM) of 0. There were statistically significant in positive rate of Hp culture among these groups (χ2=124.00, P<0.001). In addition, the successful rates of Hp eradication in PM, IM, NM and RM genotypes were 84.2% (32/38), 53.8% (14/26), 67.8% (40/59), and 0, respectively, with significant differences (χ2=11.35, P=0.010); those in IM genotype was significantly lower than that in PM genotype (P=0.011). With the same standard triple Hp eradicative regimen, the successful rate of Hp eradication for IM type was 8/19, which was lower than that of PM (80.0%, 24/30) and NM type (77.3%, 34/44) (P=0.007 and 0.007, respectively). There was a significant difference in the efficacy of Hp eradication treatment among different genotypes (χ2=9.72, P=0.008). According to the clarithromycin susceptibility result, the successful rate of Hp eradication treatment for IM genotype was 4/15 in the sensitive group and 4/4 in the drug-resistant group (χ2=6.97, P=0.018). Conclusions: The genetic polymorphism of CYP2C19 in children is closely related to the efficacy of Hp eradication treatment. PM has a higher successful rate of eradication treatment than the other genotypes.

Pharmacogenetic Testing for the Pediatric Gastroenterologist: Actionable Drug-Gene Pairs to Know.

Gastroenterologists represent some of the earlier adopters of precision medicine through pharmacogenetic testing by embracing upfront genotyping for thiopurine S-methyltransferase nucleotide diphosphatase (TPMT) before prescribing 6-mercaptopurine or azathioprine for the treatment of inflammatory bowel disease. Over the last two decades, pharmacogenetic testing has become more readily available for other genes relevant to drug dose individualization. Common medications prescribed by gastroenterologists for conditions other than inflammatory bowel disease now have actionable guidelines, which can improve medication efficacy and safety; however, a clear understanding of how to interpret the results remains a challenge for many clinicians, precluding wide implementation of genotype-guided dosing for drugs other than 6-mercaptopurine and azathioprine. Our goal is to provide a practical tutorial on the currently available pharmacogenetic testing options and a results interpretation for drug-gene pairs important to medications commonly used in pediatric gastroenterology. We focus on evidence-based clinical guidelines published by the Clinical Pharmacogenetics Implementation Consortium (CPIC®) to highlight relevant drug-gene pairs, including proton pump inhibitors and selective serotonin reuptake inhibitors and cytochrome P450 (CYP) 2C19, ondansetron and CYP2D6, 6-mercaptopurine and TMPT and Nudix hydrolase 15 (NUDT15), and budesonide and tacrolimus and CYP3A5.

Evaluation of Drug-Drug Interaction Potential of Enarodustat (JTZ-951) Using a Cytochrome P450 Probe Cocktail.

The drug interaction potential of enarodustat (doses: 25, 50mg) on the activity of cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, and 3A4 was evaluated after once-daily administration for 15 days in a phase 1 multiple-ascending-dose study in healthy subjects. Probe substrates specific for the enzymes, i.e.,caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A4), were administered orally as a cocktail with (day15) and without (day -3) enarodustat. Drug interaction was based on geometric mean maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve from the time of dosing to infinity (AUCinf ) ratios (day 15/day -3) for CYP1A2, 2C9, 2C19, 2D6, 3A4, and urinary excretion of dextromethorphan metabolite dextrorphan for CYP2D6. At the 2 enarodustat doses, for caffeine, the geometric mean ratios (range) for Cmax and AUCinf were 0.99-1.06 and 1.61-1.63, respectively. The ratios for peak concentrations and total exposures were 0.98-1.07 and 0.71-1.78 for tolbutamide and omeprazole, respectively. For dextrorphan the Cmax and AUCinf ratios were 0.83-0.90 and 1.02-1.04, respectively. The mean dextrorphan cumulative amount excreted into the urine from the time of dosing to 24 hours values on day -3 and day 15 were 8.25 mg and 8.20 mg at the lower dose, and 9.40 mg and 9.51 mg at the higher dose. The ratios for midazolam Cmax and AUCinf were 1.42-1.63. Overall, there was a lack of enarodustat dose dependency regarding the geometric mean ratios and 90% confidence intervals and urinary excretion of dextrorphan. There were some cases where the 90% confidence intervals at the 2 enarodustat doses were outside the 0.80-1.25 range, but changes in the geometric mean ratios were all <2-fold.