CYP3A5 Genetic Variants Research Articles

Exploring the Knowledge, Attitude, and Practice of Sudanese Medical Doctors Towards Tacrolimus, at Ahmed Gasim Hospital, Kidney Transplant Center Unit, Khartoum, Sudan (2022 – 2023)

Tacrolimus is one of the most commonly prescribed immunosuppressive drugs that varies between individuals depending on different ethnic groups, the presence of different CYP3A5 genetic variants, and the duration of time since the transplantation, which makes targeting optimal tacrolimus concentration levels more challenging. This study aimed to explore the knowledge, attitude, and practice of Sudanese medical doctors towards Tacrolimus. An observational, cross-sectional study was conducted on the Sudanese medical doctors in the nephrology clinic at Ahmed Gasim Hospital, Kidney Transplant Center Unit, Khartoum, Sudan, who were in direct contact with kidney transplant patients under tacrolimus treatment. Data were collected using a questionnaire modified to record the pharmacogenomic impact. The data were analyzed using a statistical package for social sciences (SPSS). Total of 15 medical doctors, Female 8 (53.3%) and male 7 (46.7%) with mean ± SD age of 31.60 ± (3.906). All of them were currently practicing in governmental hospitals (n=15; 83.3%), private hospitals (n=2; 11.1%), and private clinics (n=1; 6.7%). There were 67% of the medical doctors had high knowledge about the genetic profile of the patient's impact on the tacrolimus trough concentrations, while 66.7% of the medical doctors had low attitude levels toward tacrolimus. The observations among the different Sudanese ethnic groups tacrolimus trough concentrations were found to be variable, as Arabs and Fulani were observed to have low trough concentrations (n=6; 40%), while Nuba and Beja were observed to have high trough concentrations (n=5; 33.3%), instead of fur observed to had fluctuations (n=2; 13.3%). A significant correlation between practice toward tacrolimus with the location of practice, doctor specialty, and years of experience was found (P value ≤ 0.05). The medical doctors exerted a high level of knowledge about the impact of the genetic profile (metabolic alleles) in the dosing and dose adjustment of tacrolimus.

Composite CYP3A (CYP3A4 and CYP3A5) phenotypes and influence on tacrolimus dose adjusted concentrations in adult heart transplant recipients.

CYP3A5 genetic variants are associated with tacrolimus metabolism. Controversy remains on whether CYP3A4 increased [*1B (rs2740574), *1 G (rs2242480)] and decreased function [*22 (rs35599367)] genetic variants provide additional information. This retrospective cohort study aims to address whether tacrolimus dose-adjusted trough concentrations differ between combined CYP3A (CYP3A5 and CYP3A4) phenotype groups. Heart transplanted patients (n = 177, between 2008 and 2020) were included and median age was 54 years old. Significant differences between CYP3A phenotype groups in tacrolimus dose-adjusted trough concentrations were found in the early postoperative period and continued to 6 months post-transplant. In CYP3A5 nonexpressers, carriers of CYP3A4*1B or *1 G variants (Group 3) compared to CYP3A4*1/*1 (Group 2) patients were found to have lower tacrolimus dose-adjusted trough concentrations at 2 months. In addition, significant differences were found among CYP3A phenotype groups in the dose at discharge and time to therapeutic range while time in therapeutic range was not significantly different. A combined CYP3A phenotype interpretation may provide more nuanced genotype-guided TAC dosing in heart transplant recipients.

CYP3A5 genetic variants and their associations with carbamazepine and valproic acid response in Malaysian epileptic patients.

Epilepsy is a common chronic neurological condition characterized by recurrent seizures. Approximately 30 - 40% of epileptic patients do not respond to antiepileptic drugs. Previous studies suggest that CYP3A5 polymorphisms affect carbamazepine metabolism. To examine this hypothesis, in the present study, the associations between CYP3A5 variants (rs776746 and rs1419745) and response to carbamazepine and valproic acid monotherapy in Malaysian epileptic patients were evaluated. A total of 288 Malaysian epileptic patients were recruited and further reviewed, of whom 63 patients were on carbamazepine monotherapy, and 85 patients were on valproic acid monotherapy. There was no patient with drug hypersensitivity syndrome within the population. Subjects were genotyped by using Sequenom MassARRAY platform. This study found a significant association of CYP3A5 rs776746 with the carbamazepine treatment response in total patients (p=0.026) and Malay ethnic subgroup (p=0.006). In addition, a marginal significant association of CYP3A5 rs1419745 with carbamazepine treatment response was reported in the Malays. Similarly, CYP3A5 rs776746 was associated with valproic acid response in total patients (p=0.037) and Malays (marginal p=0.05). Our findings suggest that CYP3A5 polymorphisms affect carbamazepine and valproic acid response in Malaysian epileptic patients.

Genetic polymorphisms of cytochrome P450 enzymes: CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 in the Croatian population.

Data on the frequency of pharmacogenetic polymorphisms in the Croatian population are limited. We determined and analyzed frequencies for the most important CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 genetic variants in the Croatian population. 2637 subjects were included. Genotyping was performed by real-time polymerase chain reaction (PCR) using TaqMan® DME or TaqMan® SNP Genotyping Assays, and by PCR, and PCR-RFLP analysis. For CYP2C9, allele frequencies of *2 and *3 variant were 14.5% and 7.6%, respectively. Among them, 3.98% of subjects were predicted to be poor metabolizers. For CYP2C19, the most frequent variant alleles were *2 (14.8%), and *17 (23.7%), while 2.4% of subjects were predicted to be poor metabolizers, and 5.39% were homozygous carriers of *17 predicted to be ultrarapid metabolizers (UM). For CYP2D6, the frequencies of tested variant alleles were *3 (2.2%), *4 (17.4%), *5 (1%), *6 (1.1%), and *41 (10.8%). Out of these, 5.59% were predicted to be poor metabolizers, 3.19% were classified as UM while 1.0% were carriers of variant alleles duplications (undefined phenotype). For CYP3A4 allele frequencies of *1B and *22 variants were 1.4% and 2.7%, respectively. Allele frequency of CYP3A5*3 was 95.5%. Analyzing CYP3A cluster according to the combination of CYP3A4*22 and CYP3A5*3 revealed 5.34% of subjects to be poor metabolizers, while 8.66% were classified as extensive metabolizers. The frequency of the CYP allelic variants, genotypes, and predicted phenotypes in the Croatian population is in accordance with the other European populations, between the values of published data for Middle European and Mediterranean populations.

The potential implication of SCN1A and CYP3A5 genetic variants on antiepileptic drug resistance among Egyptian epileptic children

PurposeDespite the advances in the pharmacological treatment of epilepsy, pharmacoresistance still remains challenging. Understanding of the pharmacogenetic causes is critical to predict drug response hence providing a basis for personalized medications. Genetic alteration in activity of drug target and drug metabolizing proteins could explain the development of pharmacoresistant epilepsy. So the aim of this study was to explore whether SCN1A c.3184 A/G (rs2298771) and CYP3A5*3 (rs776746) polymorphisms could serve as genetic based biomarkers to predict pharmacoresistance among Egyptian epileptic children. MethodsGenotyping of SCN1A c.3184 A/G and CYP3A5*3 polymorphisms using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was performed in 65 healthy control subjects and 130 patients with epilepsy, of whom 50 were drug resistant and 80 were drug responsive. ResultsThere was a significant higher frequency of the AG genotype (p=0.001) and G allele (p=0.006) of SCN1A polymorphism in epileptic patients than in controls. Also their frequency was significantly higher in drug resistant patients in comparison with drug responders (p=0.005 and 0.054 respectively). No significant association between CYP3A5*3 polymorphism and drug-resistance was found. ConclusionsOverall, results confirmed the claimed role of SCN1A c.3184 A/G polymorphism in epilepsy and moreover in development of pharmacoresistance among Egyptian epileptic children. CYP3A5*3 variants have no contributing effect on pharmacoresistance among Egyptian epileptic children.

Interindividual Variations in Aprepitant Plasma Pharmacokinetics in Cancer Patients Receiving Cisplatin-Based Chemotherapy for the First Time

The pharmacokinetics of aprepitant, a neurokinin-1 receptor antagonist, have not been fully evaluated in clinical settings. The aim of this study was to characterize the plasma pharmacokinetics of aprepitant and reveal their influence of laboratory tests and cytochrome P450 (CYP) 3A5 gene polymorphisms in cancer patients. Forty-four Japanese cancer patients receiving cisplatin-based chemotherapy for the first time following oral aprepitant (125 mg on day 1 and 80 mg on days 2 and 3) were enrolled. The patients did not have gastrointestinal disease and the clinical laboratory values were within their normal reference levels. The plasma concentrations of aprepitant 24 (day 2 predose), 72, and 120 h after the first aprepitant administration were determined using LC-MS/MS. The relationships between plasma exposure to aprepitant and body weight, clinical laboratory values, age, gender, or CYP3A5*3 were investigated. The median and interquartile ranges of the 120-h area under the plasma concentration time curve (AUC)(0-120) of aprepitant were 73215 and 55518-91121 ng h/mL. The coefficient of variation value for aprepitant AUC(0-120) was 53%. The AUC(0-120) of aprepitant was correlated with the levels of total bilirubin and serum albumin, respectively (r=0.454, p<0.01 and r=0.287, p=0.06), but not with other non-genetic factors and CYP3A5 genetic variants in a univariate analysis. The AUC(0-120) of aprepitant was significantly correlated with the level of total bilirubin (adjusted R(2)=0.187, p<0.01) in a multivariate analysis. In conclusion, the plasma pharmacokinetics of aprepitant varied markedly in cancer patients receiving cisplatin-based chemotherapy for the first time and were correlated with the level of total bilirubin.

Plasma Letrozole Concentrations in Postmenopausal Women With Breast Cancer Are Associated With CYP2A6 Genetic Variants, Body Mass Index, and Age

The associations between plasma letrozole concentrations and CYP2A6 and CYP3A5 genetic variants were tested in the Exemestane and Letrozole Pharmacogenomics (ELPH) trial. ELPH is a multicenter, open-label prospective clinical trial in women randomly assigned (n≈250 in each arm) to receive 2 years of treatment with either oral letrozole (2.5 mg/day) or oral exemestane (25 mg/day). CYP2A6 and CYP3A showed effects on letrozole metabolism in vitro. DNA samples were genotyped for variants in the CYP2A6 and CYP3A5 genes. Plasma letrozole concentrations showed high interpatient variability (>10-fold) and were associated significantly with CYP2A6 genotypes (P<0.0001), body mass index (BMI) (P<0.0001), and age (P=0.0035). However, CYP3A5 genotypes showed no association with plasma letrozole concentrations. These data suggest that CYP2A6 is the principal clearance mechanism for letrozole in vivo. CYP2A6 metabolic status, along with BMI and age, may serve as a biomarker of the efficacy of letrozole treatment or a predictor of adverse effects.

Genetic Variants ofCYP3A4andCYP3A5in Cynomolgus and Rhesus Macaques

Cynomolgus and rhesus macaques are frequently used in preclinical trials due to their close evolutionary relationships to humans. We conducted an initial screening for genetic variants in cynomolgus and rhesus macaque genes orthologous to human CYP3A4 and CYP3A5. Genetic screening of 78 Indochinese and Indonesian cynomolgus macaques and 34 Chinese rhesus macaques revealed a combined total of 42 CYP3A4 genetic variants, including 12 nonsynonymous variants, and 34 CYP3A5 genetic variants, including nine nonsynonymous variants. Four of these nonsynonymous variants were located at substrate recognition sites or the heme-binding region, domains essential for protein function, including c.886G>A (V296M) and c.1310G>A (S437N) in CYP3A4 and c.1437C>G (N479K) and c.1310G>C (T437S) in CYP3A5. The mutant proteins of these genetic variants were expressed in Escherichia coli and purified. Metabolic activity of these proteins measured using midazolam and nifedipine as substrates showed that none of these protein variants substantially influences the drug-metabolizing capacity of CYP3A4 or CYP3A5 protein. In Indonesian cynomolgus macaques, we also found IVS3+1delG in CYP3A4 and c.625A>T in CYP3A5, with which an intact protein cannot be produced due to a frameshift generated. Screening additional genomes revealed that two of 239 animals and three of 258 animals were heterozygous for IVS3+1delG of CYP3A4 and c.625A>T of CYP3A5, respectively. Some genetic variants were unevenly distributed between Indochinese and Indonesian cynomolgus macaques and between cynomolgus and rhesus macaques. Information on genetic diversity of macaque CYP3A4 and CYP3A5 presented here could be useful for successful drug metabolism studies conducted in macaques.