CYP3A5 Polymorphisms Research Articles

Personalized Medicine of flecainide (The Impact of the CYP2D6 and CYP1A2 Polymorphism on Responses to Flecainide)

Flecainide is an antiarrhythmic drug (AAD) class IC that has a narrow therapeutic index. The enzymes CYP2D6 and CYP1A2 are thought to catalyse the metabolism of this medication. This gene's polymorphism permits metabolic adjustments and modifies the pharmacokinetic profile. The objective of this review is to elucidate the impact of CYP2D6 and CYP1A2 gene polymorphisms on the pharmacological response to flecainide within the human body. Using the search terms "flecainide and CYP2D6; "flecainide and CYP1A2," papers on PubMed and Science Direct were found for the review. When the terms "flecainide and CYP2D6" were searched for in PubMed for all publications published between 2000 and 2023, 23 results were identified; when the same terms were searched on SD (Research article & English version), 97 results were found, just 13 of which were open access. With the keyword "flecainide and CYP1A2" in PubMed, a search of all articles published from 1995 to 2023 there were 7 articles and 52 articles in SD (Research article & English version), meanwhile open access were 8 articles. We add several articles other than PubMed and SD. The kinetic profile of flecainide is influenced by CYP2D6 gene polymorphism, however the effect of CYP1A2 gene polymorphism on flecainide is unknown due to a lack of studies.

Impact of Pharmacogenetic Testing on Clozapine Treatment Efficacy in Patients with Treatment-Resistant Schizophrenia.

Managing schizophrenia with clozapine poses a significant challenge due to prevalent therapeutic failures. The increasing interest in personalized medicine underscores the importance of integrating pharmacogenetic information for effective pharmacotherapeutic monitoring in patients. The objective of this study was to explore the correlation between DRD2, HTR2A, SLC6A4, CYP1A2, and ABCB1 polymorphisms and clozapine response in 100 patients with Treatment-Resistant Schizophrenia. Different scales such as the Positive and Negative Syndrome Scale (PANSS), the Warwick-Edinburgh Mental Wellbeing Scale (SWEMWBS), the Global Assessment of Functioning Scale (GAF), the Brief Negative Symptom Scale (BNSS), and pharmacokinetic parameters were used to analyse the efficacy of the treatment. Patients who exclusively responded to clozapine compared to the patients with augmentation strategies exhibited distinctive features, such as lower doses, plasma levels, and presented less-pronounced symptomatology. Genetic associations were explored, highlighting SLC6A4, HTR2A, and the *1F/*1F polymorphism for the CYP1A2 gene.

Impact of CYP1A1 variants on the risk of acute lymphoblastic leukemia: evidence from an updated meta-analysis

ObjectiveOur study aimed to investigate the association between cytochrome P450 1A1 (CYP1A1) polymorphisms (T3801C and A2455G) and acute lymphoblastic leukemia (ALL) risk, considering genetic models and ethnicity.Materials and methodsPubMed, Embase, Web of Knowledge, Scopus, and the Cochrane electronic databases were searched using combinations of keywords related to CYP1A1 polymorphisms and the risk of ALL. Studies retrieved from the database searches underwent screening based on strict inclusion and exclusion criteria.ResultsIn total, 2822 cases and 4252 controls, as well as 1636 cases and 2674 controls of the C3801T and A2455G variants of CYP1A1, respectively, were included in this meta-analysis. The T3801C polymorphism of CYP1A1 significantly increases the risk of ALL, particularly those observed in Asian and Hispanic populations, independent of age. Similarly, the A2455G polymorphism of CYP1A1 plays a significant role in the susceptibility to ALL in all genetic models, except the heterozygous form. This association was observed mainly in mixed populations and in both children and adults (except in the heterozygous model).ConclusionOur comprehensive analysis indicates that the T3801 and A2455G polymorphisms of CYP1A1 may increase the risk of ALL depending on ethnicity. Therefore, both variants should be considered promising biomarkers for ALL risk. Further large-scale investigations are necessary to assess other factors, such as gene-gene or gene-environment interactions.

The prevalence of ADSL (rs3788579) and CYP1A2 (rs17861162) polymorphisms in female breast cancer patients in North-West Iran

IntroductionBreast cancer is a prevalent and significant contributor to cancer-related mortality among women worldwide. Its increasing incidence, especially in regions like North-West Iran, necessitates a deeper understanding of genetic factors contributing to its development. Genetic alterations, particularly single nucleotide polymorphisms (SNPs), are implicated in breast cancer susceptibility, making investigation in this context crucial. This study explores the role of CYP1A2-rs17861162 and ADSL-rs3788579 SNPs in breast cancer risk among Iranian women.MethodsThis study involved 200 female breast cancer patients and 200 healthy controls in North-West Iran. DNA was extracted from blood samples, and PCR–RFLP was used for genotyping the CYP1A2 and ADSL genes.ResultsThe CYP1A2-rs17861162 SNP exhibited a shift from the C allele to the G allele in breast cancer patients, resulting in a 21.7% decrease in CC genotype frequency and a 21.6% and 77.8% increase in CG and GG genotypes, respectively, compared to controls. In ADSL-rs3788579 SNP, breast cancer patients had a significantly higher prevalence of the T allele, with a 28.5% increase compared to controls. In healthy participants, CC was most common, while in the breast cancer group, TT was most common.ConclusionThis study highlights significant genetic alterations in CYP1A2-rs17861162 and ADSL-rs3788579 SNPs among breast cancer patients in North-West Iran, suggesting their potential as diagnostic and prognostic biomarkers. Further research is warranted to elucidate the precise mechanisms underlying their contributions to breast cancer susceptibility in this population.

CYP1A2*F Polymorphism Contributes at Least Partially to the Variability of Plasma Levels of Dehydroaripiprazole, an Active Metabolite of Aripiprazole, in Schizophrenic Patients.

The relationship between CYP1A2 polymorphisms and the steady-state plasma levels of aripiprazole and its active metabolite, dehydroaripiprazole, were investigated in Japanese schizophrenic patients. It has been implied that cytochrome P450 (CYP) 1A2 may play a role in the metabo-lism of aripiprazole. Genetic variations in the CYP1A2 gene have been reported. The authors investigated the relationship between 2 CYP1A2 polymorphisms, CYP1A2*C (-3860G>A) and CYP1A2*F (-163C>A), and the steady-state plasma levels/dose (C/D) ratios of aripiprazole and dehydroaripiprazole in Japanese schizophrenic patients. All 89 subjects (46 males and 43 females) had been receiving 2 fixed daily doses of aripiprazole (24 mg; n=56 and 12 mg: n=33) for more than 2 weeks. No other drugs were used except flunitrazepam and biperiden. The plasma drug levels were determined by LC/MS/MS. These CYP1A2 polymorphisms were detected using polymerase chain reaction analysis. The mean C/D ratios of dehydroaripiprazole were significantly (P < 0.05) lower in patients with the A/A allele of CYP1A2*F than in those without the allele. No differences were found in the values of aripiprazole and the combination of aripiprazole and dehydroaripiprazole among the CYP1A2*F genotype. There were no differences in the values of aripiprazole, dehydroaripiprazole, or the combination of the 2 compounds among the CYP1A2*C genotype. The absence of the A allele of CYP1A2*F was correlated with the mean C/D ratios of dehydroaripiprazole (standardized partial correlation coefficient = 0.276, P < 0.01) by multiple regression analysis. The findings of this study suggest that the CYP1A2*F polymorphism contributes at least partially to the variability in the steady-state plasma levels of dehydroaripiprazole.

Genetic CYP2A6 Polymorphism May Worsen Glycohemoglobin Levels: Study among Javanese Indonesian Smokers

We have examined the inactive CYP2A6 alleles gene, including CYP2A6*4, CYP2A6*7, and CYP2A6*9, associated with glycohemoglobin levels among Javanese Indonesian smokers. There are 106 smokers participating in this study. Due to the number of cigarettes smoked per day, there are three groups of smokers: light, intermediate, and heavy smokers, with 98.7% being light and intermediated smokers while the rest are heavy smokers. All participants had smoked for more than 10 years, indicating they had been exposed to nicotine for a long time. Based on their genotype, there were four groups of smokers, including fast, intermediate, slow, and poor metabolizers. Most fast and intermediate metabolizers have HbA1c levels in the normal range (&lt;5.7). On the other hand, most slow metabolizers have Hb1c levels &gt;5.7, and all fast metabolizers have HbA1c levels &gt;5,7, indicating that they the prediabetes and diabetes. The chi-square test showed a relationship between CYP2A6 polymorphism and HbA1c levels among the participants (P-value 0.000 &lt;0.005 and χ2=54.6, df=1). The presence of an inactive allele will worsen the HbA1c levels in smokers.

Comparative Analysis of Machine Learning Algorithms Evaluating the Single Nucleotide Polymorphisms of Metabolizing Enzymes with Clinical Outcomes Following Intravenous Paracetamol in Preterm Neonates with Patent Ductus Arteriosus.

Pharmacogenomics has been identified to play a crucial role in determining drug response. The present study aimed to identify significant genetic predictor variables influencing the therapeutic effect of paracetamol for new indications in preterm neonates. Paracetamol has recently been preferred as a first-line drug for managing Patent Ductus Arteriosus (PDA) in preterm neonates. Single Nucleotide Polymorphisms (SNPs) in CYP1A2, CYP2A6, CYP2D6, CYP2E1, and CYP3A4 have been observed to influence the therapeutic concentrations of paracetamol. The purpose of this study was to evaluate various Machine Learning Algorithms (MLAs) and bioinformatics tools for identifying the key genotype predictor of therapeutic outcomes following paracetamol administration in neonates with PDA. Preterm neonates with hemodynamically significant PDA were recruited in this prospective, observational study. The following SNPs were evaluated: CYP2E1*5B, CYP2E1*2, CYP3A4*1B, CYP3A4*2, CYP3A4*3, CYP3A5*3, CYP3A5*7, CYP3A5*11, CYP1A2*1C, CYP1A2*1K, CYP1A2*3, CYP1A2*4, CYP1A2*6, and CYP2D6*10. Amongst the MLAs, Artificial Neural Network (ANN), C5.0 algorithm, Classification and Regression Tree analysis (CART), discriminant analysis, and logistic regression were evaluated for successful closure of PDA. Generalized linear regression, ANN, CART, and linear regression were used to evaluate maximum serum acetaminophen concentrations. A two-step cluster analysis was carried out for both outcomes. Area Under the Curve (AUC) and Relative Error (RE) were used as the accuracy estimates. Stability analysis was carried out using in silico tools, and Molecular Docking and Dynamics Studies were carried out for the above-mentioned enzymes. Two-step cluster analyses have revealed CYP2D6*10 and CYP1A2*1C to be the key predictors of the successful closure of PDA and the maximum serum paracetamol concentrations in neonates. The ANN was observed with the maximum accuracy (AUC = 0.53) for predicting the successful closure of PDA with CYP2D6*10 as the most important predictor. Similarly, ANN was observed with the least RE (1.08) in predicting maximum serum paracetamol concentrations, with CYP2D6*10 as the most important predictor. Further MDS confirmed the conformational changes for P34A and P34S compared to the wildtype structure of CYP2D6 protein for stability, flexibility, compactness, hydrogen bond analysis, and the binding affinity when interacting with paracetamol, respectively. The alterations in enzyme activity of the mutant CYP2D6 were computed from the molecular simulation results. We have identified CYP2D6*10 and CYP1A2*1C polymorphisms to significantly predict the therapeutic outcomes following the administration of paracetamol in preterm neonates with PDA. Prospective studies are required for confirmation of the findings in the vulnerable population.

Effect of CYP3A4/5, ABCB1 gene polymorphisms on the residual equilibrium concentration of apixaban and bleeding in patients with non-valvular atrial fibrillation and deep vein thrombosis

Effect of CYP3A4/5, ABCB1 gene polymorphisms on the residual equilibrium concentration of apixaban and bleeding in patients with non-valvular atrial fibrillation and deep vein thrombosis

The Genetic Polymorphisms of CYP3A4*1G and CYP3A5*3 in Javanese Indonesian Population

Polymorphisms of CYP3A4*1G and CYP3A5*3 affect the pharmacokinetic profile of various drugs, e.g., fentanyl, tacrolimus, diltiazem, simvastatin. Tetra-primer amplification refractory mutation system-polymerase chain (ARMS-PCR) is a simple and economical method for SNP determination. The polymorphisms in the CYP3A4*1G and CYP3A5*3 genes have not yet been examined using this method in Javanese Indonesian. Our aim was to determine the frequency of polymorphisms in the CYP3A4*1G and CYP3A5*3 genes in Indonesian Javanese using the ARMS-PCR method. Eighty-six patients at the Kalasan Community Health Centre in Yogyakarta, Indonesia, were chosen based on the inclusion criteria, which is Javanese ancestry. They gave their informed consent to blood collection by completing a form. Genetic variants were detected using Tetra-primer amplification refractory mutation system-polymerase chain (ARMS-PCR). The chi-square test was used to determine genotype deviations from Hardy-Weinberg equilibrium, with a significant threshold of 0.05. For homozygous wild types, CYP3A4 *1/*1 dominated overall among study participants (73.35%), whereas for CYP3A5*3/*3, homozygous mutants were more prevalent (83.72%). Hardy-Weinberg equilibrium is consistent with genotype frequencies (p &gt; 0.005). One participant carried a homozygous mutation for both CYP3A4*1G and CYP3A5*3, while the other 49 subjects were heterozygous for CYP3A4*1G and homozygous mutant for CYP3A5*3, which is the highest number of SNP combinations. The findings of the current investigation demonstrate that the population has the highest proportion of homozygous CYP3A4*1G wild-types (CYP3A4*1/*1) and homozygous mutants for CYP3A5*3 (CYP3A5*3/*3)

CYP3A5 influences oral tacrolimus pharmacokinetics and timing of acute kidney injury following allogeneic hematopoietic stem cell transplantation.

Introduction: Polymorphisms in genes responsible for the metabolism and transport of tacrolimus have been demonstrated to influence clinical outcomes for patients following allogeneic hematologic stem cell transplant (allo-HSCT). However, the clinical impact of germline polymorphisms specifically for oral formulations of tacrolimus is not fully described. Methods: To investigate the clinical impact of genetic polymorphisms in CYP3A4, CYP3A5, and ABCB1 on oral tacrolimus pharmacokinetics and clinical outcomes, we prospectively enrolled 103 adult patients receiving oral tacrolimus for the prevention of graft-versus-host disease (GVHD) following allo-HSCT. Patients were followed in the inpatient and outpatient phase of care for the first 100 days of tacrolimus therapy. Patients were genotyped for CYP3A5 *3 (rs776746), CYP3A4 *1B (rs2740574), ABCB1 exon 12 (rs1128503), ABCB1 exon 21 (rs2032582), ABCB1 exon 26 (rs1045642). Results: Expression of CYP3A5 *1 was highly correlated with tacrolimus pharmacokinetics in the inpatient phase of care (p < 0.001) and throughout the entirety of the study period (p < 0.001). Additionally, Expression of CYP3A5 *1 was associated with decreased risk of developing AKI as an inpatient (p = 0.06). Variants in ABCB1 were not associated with tacrolimus pharmacokinetics in this study. We were unable to discern an independent effect of CYP3A4 *1B or *22 in this population. Conclusion: Expression of CYP3A5 *1 is highly influential on the pharmacokinetics and clinical outcomes for patients receiving oral tacrolimus as GVHD prophylaxis following allo-HSCT.

Influence of Cyp3A4, Cyp3A5 and ABCB1 Polymorphisms on Tacrolimus Concentrations and Rejection Risk in Indian Kidney Transplant Recipients

Background: Tacrolimus metabolism is known to be determined by gene polymorphisms. Cyp3A5 genotype has most widely been seen to be associated with tacrolimus metabolism. Studies on other genes have produced mixed results. Objective: We studied the association of three polymorphisms CYP3A4*1B (-392 G&gt;A), CYP3A5 (6986 A&gt;G), and ABCB1 (3435 T&gt;C) on tacrolimus levels and their association with either rejection or nephrotoxicity (infection or tacrolimus toxicity) in renal transplant recipients from India. Materials and Methods: In this prospective cohort study, patients who underwent kidney transplantation between July 2018 and July 2023 were studied. Inclusion criteria: Patients who underwent Kidney Transplantation and were (i) on tacrolimus-based immunosuppression and (ii) not on medications known to interact with calcineurin inhibitors, such as ketoconazole, phenytoin, and diltiazem, were studied. Tacrolimus levels, tacrolimus concentration/dose (C/D) and tacrolimus C/D per kg body weight, at monthly time points posttransplant for 6 months and biopsy-proven rejection, infection, tacrolimus toxicity, and acute tubular necrosis data were collected. Results: Three hundred and twenty-seven patients were included in the study. Two hundred and fifty-seven were male and 70 were female. A total of 1402 tacrolimus samples were collected, with an average of 3.2 ± 2.1 samples per patient. Tacrolimus levels were significantly lower in the Cyp3A5 AG and AA GG genotypes versus GG (5.27 ± 2.95 and 6.22 ± 2.79 vs. 8.05 ± 4.83, P &lt; 0.001) as were C/D (3.45 ± 2.29 and 3.37 ± 1.91 vs. 6.47 ± 4.44, P &lt; 0.001) and C/D/W (52.45 ± 33.98 and 52.19 ± 32.61 vs. 98.09 ± 73.80, P &lt; 0.001). Cyp3A5 AA and AG had higher rejection rates than GG (20% vs. 13 vs. 8%, P = 0.03). The relative risk of rejection with A versus G polymorphism was 1.9 (confidence interval: 1.03–3.58), P = 0.03. Cyp3A4 and ABCB1 polymorphism studies did not show any association with the parameters studied. Conclusion: Our study showed that Cyp3A5 gene polymorphisms were significantly associated with tacrolimus metabolism, rejection episodes, and rejection risk. Cyp3A4 and ABCB1 were not significantly associated with the parameters studied.

Exploring inter-ethnic and inter-patient variability and optimal dosing of osimertinib: a physiologically based pharmacokinetic modeling approach.

Purpose: This study aimed to develop and validate a physiologically based pharmacokinetic (PBPK) model for osimertinib (OSI) to predict plasma trough concentration (Ctrough) and pulmonary EGFRm+ (T790M and L858R mutants) inhibition in Caucasian, Japanese, and Chinese populations. The PBPK model was also utilized to investigate inter-ethnic and inter-patient differences in OSI pharmacokinetics (PK) and determine optimal dosing regimens. Methods: Population PBPK models of OSI for healthy and disease populations were developed using physicochemical and biochemical properties of OSI and physiological parameters of different groups. And then the PBPK models were validated using the multiple clinical PK and drug-drug interaction (DDI) study data. Results: The model demonstrated good consistency with the observed data, with most of prediction-to-observation ratios of 0.8-1.25 for AUC, Cmax, and Ctrough. The PBPK model revealed that plasma exposure of OSI was approximately 2-fold higher in patients compared to healthy individuals, and higher exposure observed in Caucasians compared to other ethnic groups. This was primarily attributed to a lower CL/F of OSI in patients and Caucasian. The PBPK model displayed that key factors influencing PK and EGFRm+ inhibition differences included genetic polymorphism of CYP3A4, CYP1A2 expression, plasma free concentration (fup), albumin level, and auto-inhibition/induction on CYP3A4. Inter-patient PK variability was most influenced by CYP3A4 variants, fup, and albumin level. The PBPK simulations indicated that the optimal dosing regimen for patients across the three populations of European, Japanese, and Chinese ancestry was OSI 80mg once daily (OD) to achieve the desired range of plasma Ctrough (328-677nmol/L), as well as 80mg and 160mg OD for desirable pulmonary EGFRm+ inhibition (>80%). Conclusion: In conclusion, this study's PBPK simulations highlighted potential ethnic and inter-patient variability in OSI PK and EGFRm+ inhibition between Caucasian, Japanese, and Chinese populations, while also providing insights into optimal dosing regimens of OSI.

Quit Attempts Among Smokers and its Association with CYP2A6 (rs56113850) Polymorphisms

Introduction: Nicotine serves as the primary addictive component of tobacco. While it is not a carcinogen itself, it plays an important role in encouraging smoking and ongoing exposure to numerous carcinogenic substances found in tobacco. The half-life of nicotine tends to be extended in individuals with reduced P450 2A6 activity, and smokers with lower enzyme activity frequently reduce either the intensity of their smoking or the number of cigarettes they consume when compared to individuals with 'normal' enzyme activity. Hence, a study assessed CYP2A6 polymorphisms and quit attempts among smokers. Materials and methods: 5ml of salivary samples were collected from 100 smokers and 100 nonsmokers who had visited Saveetha Dental College in April- May 2023. DNA isolation was done, followed by PCR analysis and Amplification with RFLP. Quit attempts, duration of quit attempts, and methods employed for smoking abstention were assessed using a questionnaire. The statistical association between quit attempts and CYP2A6 (rs56113850) polymorphism was done using the Chi-square test. Results: About 27.9% of smokers had an attempt to quit smoking previously; the rest of smokers (72.1%) did not make an attempt to quit the habit. About 74% smokers have the normal allele (T), the rest 26% have a variant allele (C), about 73% of non-smokers have a normal allele, and the rest 27% have a variant allele. Association between CYP2A6 allele variants and interest to quit scale showed that the normal genotype has a higher scale of interest in quitting tobacco, and the homozygous variant genotype shows the least interest towards quitting tobacco usage, suggesting that there is an association between gene polymorphism and quit attempts. Conclusion: In the present study, there is an association between quit attempts and CYP2A6 polymorphisms among the smokers who had visited the dental hospital. However, the association is not statistically significant.

Association of genetic predisposition studies in CYP1A1 polymorphism studies in acute myeloid leukemia

Cytochrome P450 Family 1 Subfamily A Member 1 (CYP1A1) gene is one of the sub-members of CYP450 family member and it encodes with the families of drug metabolizing enzyme families along with the cancers and leukemias. Among leukemias, AML is considered to be one of the important leukemia which attack the older adults. The aim of this study is to explore the role of A4889G polymorphism in CYP1A1 gene in acute myeloid leukemia (AML) in the Saudi population. This study was designed as an experimental case-control study in which 100 AML cases and 100 controls were selected. This in vivo study was carried out using genomic DNA extraction, polymerase chain reaction and agarose gel electrophoresis and then BsrDI restriction enzyme to digest the A4889G polymorphism of the PCR products. In this study, 200 subjects were digested and based on the appearance of the bands, genotypes were categorized. The attained data was used to calculate the clinical details as well as genotype analysis. The study results confirmed AG genotype (OR = 3.23, CI = 1.60–6.55, p = 0.0008), AG + GG (OR = 3.47, CI = 1.76–6.86, p = 0.0002) and GG + AA (OR = 12.47, CI = 6.18–15.17, p < 0.0001) and G vs A (OR = 3.15, CI = 1.71–5.81, p = 0.0001) were associated in AML cases. In conclusion, we confirm that A4889G polymorphism is associated with AML in the Saudi population.

CYP1A1 (RS4646421) gene polymorphism and peculiarities of immune profile in children under aerogenic exposure to benzo(a)pyrene

Introduction. The benzo(a)pyrene exposure forms the special phenotype of the immune profile in children. The study of immune system features associated with the polymorphism of detoxification genes is relevant in the conditions of health risks linked with environmental pollution.&#x0D; Materials and methods. There was performed clinical and laboratory examination of four hundred seventy nine children aged of 3–6 years. The observation group consisted of 308 children living in conditions of aerogenic exposure to benzo(a)pyrene. The comparison group included 171 children from a relatively clean territory. Determination of benzo(a)pyrene concentration in an atmospheric air and in blood was carried out by HPLC. The study of polymorphism of CYP1A1 (rs4646421) gene was carried out by real-time PCR. CD3+CD4+-lymphocyte phenotyping was performed by flow cytometry, IgG to benzo(a)pyrene – by allergosorbent testing.&#x0D; Results. Aerogenic exposure to benzo(a)pyrene at an average daily dose of 8.76•10–2 µg/(kg•day) causes an increase in the level of blood contamination with PAH, forms an imbalance of the immune profile (IgG to benzo(a)pyrene hyperproduction, CD3+CD4+-lymphocyte expression deficiency and CD4+/CD8+decrease) associated with T-allele and CT-genotype of the CYP1A1 gene (rs4646421) (OR(CI)=2.35–6.65; p&lt;0.05). Children with the CT-genotype of the CYP1A1 gene (rs4646421) are characterized by the most pronounced changes in the immune profile (excess IgG to benzo(a)pyrene; reduction of CD3+CD4+ and CD4+/CD8+ against the background of maximum blood contamination with benzo(a)pyrene in relation to other genotypic groups (OR(CI)=1.64–3.08; p&lt;0.05). &#x0D; Limitations. The limitations are related to the need to increase the sample and verify the results obtained in subsequent observations.&#x0D; Conclusion. The peculiarities of the immune profile in CT-genotype carriers of the CYP1A1 (rs4646421) gene under the conditions of aerogenic exposure to benzo(a)pyrene at a dose of 8.76•10–2 mcg/(kg•day) should include the formation of specific sensitization to benzo(a)pyrene, deficiency of cellular differentiation clusters: CD3+CD4+-lymphocytes, CD4+/CD8+ reduction associated with blood contamination with benzo(a)pyrene, which indicate the likelihood of hereditary predisposition realization and the formation of immune regulation disorders associated with exposure to benzo(a)pyrene.

Effects of pharmacogenetic profiles on pediatric pain relief and adverse events with ibuprofen and oxycodone.

Individual genetic variation may influence clinical effects for pain medications. Effects of CYP2C9, CYP3A4, and CYP2D6 polymorphisms on clinical effectiveness and safety for ibuprofen and oxycodone were studied. Primary objectives were to AU2 evaluate if allelic variations would affect clinical effectiveness and adverse events (AEs) occurrence. This pragmatic prospective, observational cohort included children aged 4 to 16 years who were seen in a pediatric emergency department with an acute fracture and prescribed ibuprofen or oxycodone for at-home pain management. Saliva samples were obtained for genotyping of allelic variants, and daily telephone follow-up was conducted for 3 days. Pain was measured using the Faces Pain Scale-Revised. We included 210 children (n = 140 ibuprofen and n = 70 oxycodone); mean age was 11.1 (±SD 3.5) years, 33.8% were female. Median pain reduction on day 1 was similar between groups [ibuprofen 4 (IQR 2,4) and oxycodone 4 (IQR 2,6), P = 0.69]. Over the 3 days, the oxycodone group experienced more AE than the ibuprofen group (78.3% vs 53.2%, P < 0.001). Those with a CYP2C9*2 reduced function allele experienced less adverse events with ibuprofen compared with those with a normal functioning allele CYP2C9*1 (P = 0.003). Neither CYP3A4 variants nor CYP2D6 phenotype classification affected clinical effect or AE. Although pain relief was similar, children receiving oxycodone experienced more AE, overall, than those receiving ibuprofen. For children receiving ibuprofen or oxycodone, pain relief was not affected by genetic variations in CYP2C9 or CYP3A4/CYP2D6, respectively. For children receiving ibuprofen, the presence of CYP2C9*2 was associated with less adverse events.

CYP3A5*3 and CYP3A4*22 Cluster Polymorphism Effects on LCP-Tac Tacrolimus Exposure: Population Pharmacokinetic Approach.

The aim of the study is to develop a population pharmacokinetic (PopPK) model and to investigate the influence of CYP3A5/CYP3A4 and ABCB1 single nucleotide polymorphisms (SNPs) on the Tacrolimus PK parameters after LCP-Tac formulation in stable adult renal transplant patients. The model was developed, using NONMEM v7.5, from full PK profiles from a clinical study (n = 30) and trough concentrations (C0) from patient follow-up (n = 68). The PK profile of the LCP-Tac formulation was best described by a two-compartment model with linear elimination, parameterized in elimination (CL/F) and distributional (CLD/F) clearances and central compartment (Vc/F) and peripheral compartment (Vp/F) distribution volumes. A time-lagged first-order absorption process was characterized using transit compartment models. According to the structural part of the base model, the LCP-Tac showed an absorption profile characterized by two transit compartments and a mean transit time of 3.02 h. Inter-individual variability was associated with CL/F, Vc/F, and Vp/F. Adding inter-occasion variability (IOV) on CL/F caused a statistically significant reduction in the model minimum objective function MOFV (p < 0.001). Genetic polymorphism of CYP3A5 and a cluster of CYP3A4/A5 SNPs statistically significantly influenced Tac CL/F. In conclusion, a PopPK model was successfully developed for LCP-Tac formulation in stable renal transplant patients. CYP3A4/A5 SNPs as a combined cluster including three different phenotypes (high, intermediate, and poor metabolizers) was the most powerful covariate to describe part of the inter-individual variability associated with apparent elimination clearance. Considering this covariate in the initial dose estimation and during the therapeutic drug monitoring (TDM) would probably optimize Tac exposure attainments.

Habitual coffee consumption and risk of dementia in older persons: modulation by CYP1A2 polymorphism.

Higher coffee consumption has been associated with reduced dementia risk, yet with inconsistencies across studies. CYP1A2 polymorphisms, which affects caffeine metabolism, may modulate the association between coffee and the risk of dementia and Alzheimer's disease (AD). We included 5964 participants of the Three-City Study (mean age 74 years-old), free of dementia at baseline when they reported their daily coffee consumption, with available genome-wide genotyping and followed for dementia over a median of 9.0 (range 0.8-18.7) years. In Cox proportional-hazards models, the relationship between coffee consumption and dementia risk was modified by CYP1A2 polymorphism at rs762551 (p for interaction = 0.034). In multivariable-adjusted models, coffee intake was linearly associated with a decreased risk of dementia among carriers of the C allele only ("slower caffeine metabolizers"; HR for 1-cup increased [95% CI] 0.90 [0.83-0.97]), while in non-carriers ("faster caffeine metabolizers"), there was no significant association but a J-shaped trend toward a decrease in dementia risk up to 3 cups/day and increased risk beyond. Thus, compared to null intake, drinking ≥ 4 cups of coffee daily was associated with a reduced dementia risk in slower but not faster metabolizers (HR [95% CI] for ≥ 4 vs. 0 cup/day = 0.45 [0.25-0.80] and 1.32 [0.89-1.96], respectively). Results were similar when studying AD and another CYP1A2 candidate polymorphism (rs2472304), but no interaction was found with CYP1A2 rs2472297 or rs2470893. In this cohort, a linear association of coffee intake to lower dementia risk was apparent only among carriers of CYP1A2 polymorphisms predisposing to slower caffeine metabolism.

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.

Association of high intra-patient variability in tacrolimus exposure with calcineurin inhibitor nephrotoxicity in kidney transplantation

Tacrolimus intra-patient variability (IPV) is a novel predictive marker for long-term kidney transplantation outcomes. We examined the association between IPV and calcineurin inhibitor (CNI) nephrotoxicity and the impact of pharmacogenes on CNI nephrotoxicity and IPV. Among kidney transplant recipients at our hospital between January 2013 and December 2015, the records of 80 patients who underwent 1-year protocol renal allograft biopsy and agreed to donate blood samples for genetic analysis were retrospectively reviewed. The cohort was divided into the low and high IPV groups based on a coefficient variability cutoff value (26.5%). In multivariate analysis, the IPV group was involved in determining CNI nephrotoxicity (HR 4.55; 95% CI 0.05–0.95; p = 0.043). The 5-year graft survival was superior in the low IPV group than in the high IPV group (100% vs 92.4% respectively, p = 0.044). Analysis of the time above therapeutic range (TATR) showed higher CNI nephrotoxicity in the high IPV with high TATR group than in the low IPV with low TATR group (35.7% versus 6.7%, p = 0.003). Genetic analysis discovered that CYP3A4 polymorphism (rs2837159) was associated with CNI nephrotoxicity (HR 28.23; 95% CI 2.2–355.9; p = 0.01). In conclusion, high IPV and CYP3A4 polymorphisms (rs2837159) are associated with CNI nephrotoxicity.