The Frequencies distribution of CYP3A5 rs776746 and ABCB1 rs1045642 polymorphisms in the west Algerian population and relationships with pharmacogenetics.

Introduction: Pharmacogenetic markers, such as the ATP Binding Cassette (ABCB1) and cytochrome P450 (CYP) 3A5 enzymes, play a crucial role in personalized medicine by influencing drug efficacy and toxicity based on individuals' or populations' genetic variations.This study aims to investigate the genetic polymorphisms of CYP3A5 (rs776746) and ABCB1 (rs1045642) in the West Algerian population and compare the genotypes and allelic distributions with those of various ethnic groups. Methods: The study involved 472 unrelated healthy subjects from the Western Algerian population. DNA genotyping was performed using TaqMan allelic discrimination assay. The variants in our population were compared to those in other ethnic groups available in the 1000 Genomes Project. Genotype and allele frequencies were calculated using the chi-square test and the Hardy-Weinberg equilibrium (HWE). Results: The minor allele frequencies were found to be 0.21 for CYP3A5 6986A and 0.34 for ABCB1 3435T. These frequencies were similar to those observed in North African populations, while notable differences were observed in comparison to certain Caucasian and African populations. Conclusion: The difference in the allelic and genotypic distribution of these polymorphisms emphasize the need for dose adjustments in drugs metabolized by CYP3A5 and transported by ABCB1 to optimize treatments outcomes.

Meta-analysis of the effects of CYP3A5*3 gene polymorphisms on tacrolimus blood concentration and effectiveness in Chinese patients with membranous nephropathy.

Objective: The study aimed to systematically evaluate the relationship between CYP3A5*3 gene polymorphisms and the blood concentration and effectiveness of tacrolimus (TAC) in patients with membranous nephropathy (MN). Methods: PubMed, Cochrane Library, Embase, Web of Science, China Biomedical, China National Knowledge Infrastructure, Wanfang, Vipshop, ReadShow, Clinical Trials Registry, and other databases were searched. Studies on the relationship between CYP3A5*3 gene polymorphism and TAC blood concentration in MN patients were collected, and meta-analysis was performed using Stata 16 software. Results: A total of eight publications were included in the study, including 498 MN patients. CYP3A5*3 gene polymorphisms are associated with tacrolimus blood levels in patients with MN. The results of the relationship between CYP3A5*3 genotype polymorphisms and tacrolimus blood trough concentrations of the AA + AG genotype were lower than those of the GG genotype at ≤1 month [WMD = -2.08, 95% CI (-2.57, -1.59), p < 0.001] and 1-6 months [WMD = -0.63, 95% CI (-0.98, -0.27), p < 0.001]; however, they were not statistically significant at ≥6 months (p = 0.211). Furthermore, the subgroup analysis revealed that the dose-adjusted concentration of tacrolimus (C0/D) of the AA + AG genotype was lower than that of the GG genotype at ≤1 month [SMD = -1.93, 95% CI (-2.79, -1.08), p < 0.001], 1-6 months [SMD = -2.25, 95% CI (-2.71, -1.79), p < 0.001], and ≥6 months [SMD = -2.36, 95% CI (-2.86, -1.86), p < 0.001]. In addition, there was no statistically significant difference in effectiveness between the two groups at 3, 6, and 12 months of TAC administration (p > 0.05). Conclusion: Serum TAC concentrations in MN patients were correlated with CYP3A5*3 genotype polymorphisms. Detection of the CYP3A5*3 genotype before the administration of TAC may provide some clinical value for optimizing the treatment of MN patients. Systematic Review Registration: https://inplasy.com/, identifier [INPLASY202430083].

Impact of CYP2D6*2A, CYP2D6*4 and CYP3A5*3 genetic polymorphisms on Bisoprolol peak concentration and clinical response in acute coronary syndrome patients.

AIMS: Acute coronary syndrome (ACS) represents a major cause of death. Bisoprolol is commonly used in the management of ACS. This study aims to investigate the impact of CYP2D6*2A, CYP2D6*4 and CYP3A5*3 genetic polymorphisms on pharmacokinetics and clinical response of bisoprolol in ACS patients. METHODS: This is an open-label cohort study that included 127 ACS patients and studied the effect of CYP3A5*3, CYP2D6*2A and CYP2D6*4 genotyping using real-time polymerase chain reaction on steady state bisoprolol plasma peak concentration analysed by high performance liquid chromatography-fluorescence detector. RESULTS: Regarding CYP3A5*3, the mean peak bisoprolol concentration for CC, CT and TT genotypes were 4.25 ± 1.20, 3.93 ± 1.10 and 1.79 ± 0.69 ng/mL, respectively (P < .001). Higher systolic (126 ± 5.47 mmHg), diastolic blood pressure (82 ± 2.73 mmHg) and heart rate (97.80 ± 3.03 beats/min) were also observed in CYP3A5*3 TT carriers (P < .05). In CYP2D6*2A, the peak concentration of bisoprolol was lower in CC carriers (3.54 ± 1 ng/mL) compared to GG (4.38 ± 1.25 ng/mL) and GC carriers (4.07 ± 1.29 ng/mL, P = .019). In CYP2D6*4, the mean bisoprolol peak concentration in CC carriers was 3.98 ± 1.31 ng/mL, which was lower than T allele carriers (4.5 ± 0.8, P = .02). No differences in heart rate, systolic, diastolic blood pressure or bisoprolol dose were observed among CYP2D6*2A or CYP2D6*4 variants. Smokers exhibited lower bisoprolol peak concentration (3.96 ± 1.2 ng/mL) compared to nonsmokers (4.55 ± 1.34 ng/mL, P = .037). CONCLUSION: There is an association between CYP3A5*3, CYP2D6*4, CYP2D6*2A variants and bisoprolol peak concentration, which may serve as a guide in the future in choosing the optimum dose of bisoprolol in ACS patients.

Tacrolimus Personalized Therapy based on CYP3A5 Genotype in Chinese Patients with Idiopathic Inflammatory Myopathies.

OBJECTIVE: Idiopathic inflammatory myopathies (IIM) are a heterogeneous and life-threatening group of diseases, especially anti-melanoma differentiation-associated gene 5 antibody positive dermatomyositis (MDA5+ DM) is reportedly strongly associated with high mortality rate. Tacrolimus (TAC) provides an excellent therapeutic option, but the trough concentration (Cmin) -outcome relationship remains unexplored. This study was undertaken to identify optimal Cmin and individualized dose based on CYP3A5 genotype for IIM patients. METHODS: 134 IIM patients with 467 Cmin were enrolled. We examined the relationship between TAC Cmin and relapses. The receiver operating characteristic analysis was used to confirm the optimal Cmin. Analyses of factors influencing Cmin were conducted. The dose requirement based on CYP3A5 genotype was confirmed. RESULTS: TAC Cmin is strongly associated with relapses. The optimal cutoff values were 5.30, 5.85, 4.85 and 5.35 ng/ml for acute, subacute, chronic and all phase IIM patients (p = 0.001, 0.013, 0.002, and < 0.001, respectively), as well as 5.35, 5.85, 5.55 and 5.85 ng/ml for acute, subacute, chronic and all phase MDA5+ DM patients (p = 0.007, 0.001, 0.036, and < 0.001, respectively). CYP3A5 genotype was one of the significant factors influencing TAC Cmin. CYP3A5 expressers required 0.059 mg/kg/d to attain the target Cmin, while nonexpressers required 0.046 mg/kg/d (p = 0.019). CONCLUSION: TAC treatment may elicit favorable outcome in patients with IIM and MDA5+ DM when Cmin exceeded 5.35 and 5.85 ng/ml, which is crucial to lower relapse rate. The individualized dose based on the CYP3A5 genotype provides a reference for TAC personalized therapy in IIM.

Pharmacogenetics of Carbamazepine: A Systematic Review on CYP3A4 and CYP3A5 Polymorphisms.

BACKGROUND AND OBJECTIVE: The association between carbamazepine (CBZ) metabolism and resistance in epilepsy and the genetic polymorphisms of CYP3A5 (rs776746 and rs15524) and CYP3A4 (rs2242480, rs2740574, rs35599367, rs12721627, and rs28371759) has been the subject of previous investigations with controversial results. We conducted a systematic review to assess the potential link between these polymorphisms and CBZ metabolism and resistance. METHODS: Identifying relevant studies, was carried out bay searching PubMed, Scopus, PharmGKB, EPIGAD, and PHARMAADME databases up until June 2023. The studies included in our analysis investigated the connection between CYP3A5 (rs776746 and rs15524) and CYP3A4 (rs2242480, rs2740574, rs35599367, rs12721627, and rs28371759) polymorphisms and CBZ metabolism and resistance. RESULTS: This review included a total of 23 studies and more than 2177 epilepsy patients. As a result the CYP3A4 (rs12721627 and rs28371759) polymorphisms are associated with reduced catalytic activity, where the CYP3A4 (rs2740574) polymorphism is linked to lower levels of CBZ-diol and decreased activity. It's been found also that the CYP3A5 (rs776746) polymorphism influences the dose-adjusted plasma levels of CBZ. CONCLUSION: Although these findings highlight the impact of genetic variations in the CYP3A4 and CYP3A5 genes on CBZ pharmacokinetics and pharmacodynamics, further studies across diverse populations are essential to enhance personalized epilepsy therapy in clinical settings.

The hidden dangers of short-term glucocorticoid use in children: A genomic analysis.

OBJECTIVE: Glucocorticoid (GC) administration has been associated with adverse drug reactions (ADRs) affecting multiple organ systems. While long-term use is widely recognized as a significant independent predictor of ADRs, it is important to note that even short-term use can lead to serious ADRs. The considerable inter-individual variability in ADRs occurrence may be influenced by genetic factors. This study, we present a case of a child who experienced significant weight gain and osteoporosis, following a brief administration of GC. METHODS: To comprehensively investigate the underlying mechanisms, we conducted a genomic analysis utilizing the whole exome sequencing (WES) technique. This analysis encompassed the examination of phase I and phase II metabolism, influx transport, efflux transport, and drug targeting. Additionally, a comprehensive analysis was conducted on a cohort of 52,119 children to determine their ABCB1 rs1045642 genotype, and an additional 37,884 children were tested for their CYP3A5 rs776746 genotype. RESULTS: The pharmacogenetic analysis unveiled the presence of a high-risk variant in ABCB1 rs1045642 and a slow metabolism variant in CYP3A5 rs776746, both of which have the potential to substantially contribute to ADRs. The findings of this study indicate that the prevalence of ABCB1 rs1045642 CT type among patients was 47.58%, with TT type accounting for 15.69 % and CC type accounting for 36.73 %. Furthermore, the distribution of CYP3A5 rs776746 CC genotype was observed in 50.54 % of individuals, while CT and TT genotypes were present in 41.15 % and 8.31 % of the population respectively. The distribution of ABCB1 and CYP3A5 genotypes among the pediatric population in China displays notable features. Specifically, for the ABCB1 rs1045642 genotype, less than 50 % of children exhibit intermediate metabotypes. Conversely, among children with the CYP3A5 rs776746 genotype, the predominant cause for enzyme activity is the slow metabolic type, accounting for up to 90 % of cases. CONCLUSIONS: Consequently, it is imperative to thoroughly evaluate the impact of allele mutation on the effectiveness and safety of glucocorticoid drugs or other medications metabolized by the ABCB1 and CYP3A5, particularly in the context of Chinese pediatric patients.

Effects of CYP3A5 Genotype on Tacrolimus Pharmacokinetics and Graft-versus-Host Disease Incidence in Allogeneic Hematopoietic Stem Cell Transplantation.

Tacrolimus (Tac) is pivotal in preventing acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT). It has been reported that genetic factors, including CYP3A5*3 and CYP3A4*22 polymorphisms, have an impact on Tac metabolism, dose requirement, and response to Tac. There is limited information regarding this topic in alloHSCT. The CYP3A5 genotype and a low Tac trough concentration/dose ratio (Tac C0/D ratio) can be used to identify fast metabolizers and predict the required Tac dose to achieve target concentrations earlier. We examined 62 Caucasian alloHSCT recipients with a fast metabolizer phenotype (C0/dose ratio ≤ 1.5 ng/mL/mg), assessing CYP3A5 genotypes and acute GVHD incidence. Forty-nine patients (79%) were poor metabolizers (2 copies of the variant *3 allele) and 13 (21%) were CYP3A5 expressers (CYP3A5*1/*1 or CYP3A5*1/*3 genotypes). CYP3A5 expressers had lower C0 at 48 h (3.7 vs. 6.2 ng/mL, p = 0.03) and at 7 days (8.6 vs. 11.4 ng/mL, p = 0.04) after Tac initiation, tended to take longer to reach Tac therapeutic range (11.8 vs. 8.9 days, p = 0.16), and had higher incidence of both global (92.3% vs. 38.8%, p < 0.001) and grade II-IV acute GVHD (61.5% vs. 24.5%, p = 0.008). These results support the adoption of preemptive pharmacogenetic testing to better predict individual Tac initial dose, helping to achieve the therapeutic range and reducing the risk of acute GVHD earlier.

Comparison of the CYP3A selective inhibitors CYP3cide, clobetasol, and azamulin for their potential to distinguish CYP3A7 activity in the presence of CYP3A4/5.

The CYP3A7 enzyme accounts for ~50% of the total CYP content in fetal and neonatal livers and is the predominant CYP involved in neonatal xenobiotic metabolism. Additionally, it is a key player in healthy birth outcomes through the oxidation of dehydroepiandrosterone (DHEA) and DHEA-S (sulfate). The amount of the other hepatic CYP3A isoforms, CYP3A4 and CYP3A5, expressed in neonates is low, but highly variable, and therefore the activity of individual CYP3A isoforms is difficult to differentiate due to their functional similarities. Consequently, a better understanding of the contribution of CYP3A7 to drug metabolism is essential to identify the risk drugs may pose to neonates and developing infants. To distinguish CYP3A7 activity from CYP3A4/5, we sought to further characterize the selectivity of the specific CYP3A inhibitors CYP3cide, clobetasol, and azamulin. We utilized three substrate probes, dibenzylfluorescein, luciferin-PPXE, and midazolam, to determine the IC50 and metabolism-dependent inhibition (MDI) properties of the CYP3A inhibitors. Probe selection had a significant effect on the IC50 values and CYP inactivation across all inhibitory compounds and enzymes. CYP3cide and azamulin were both identified as MDIs and were most specific for CYP3A4. Contrary to previous reports, we found that CP was not an MDI of CYP3A5, but was more selective for CYP3A5 over CYP3A4/7. We further investigated CYP3cide and CP's ability to differentiate CYP3A7 activity in an equal mixture of recombinant CYP3A4, CYP3A5, and CYP3A7 and our results provide confidence of CYP3cide's and CP's ability to distinguish CYP3A7 activity in the presence of the other CYP3A isoforms. Significance Statement These findings provide valuable insight regarding in vitro testing conditions to investigate the metabolism of new drug candidates and help determine drug safety in neonates. The results presented here also clearly demonstrate the effect probe selection may have on CYP3A P450 inhibition studies.

Recurrent high creatine kinase levels under clozapine treatment - a case report assessing a suspected adverse drug reaction.

Suspected adverse drug reactions (ADRs) during treatment with clozapine often prompt therapeutic drug monitoring (TDM) in clinical practice. Currently, there is no official recommendation for pharmacogenetic (PGx) testing in the context of clozapine therapy. In this case report, we demonstrate and discuss the challenges of interpreting PGx and TDM results highlighting the possibilities and limitations of both analytical methods. A 36-year-old male patient with catatonic schizophrenia was treated with clozapine. He experienced multiple hospitalizations due to elevated creatine kinase (CK) levels (up to 9000 U/L, reference range: 30-200 U/L). With no other medical explanation found, physicians suspected clozapine-induced ADRs. However, plasma levels of clozapine were consistently low or subtherapeutic upon admission, prompting us to conduct a PGx analysis and retrospectively review the patient's TDM data, progress notes, and discharge reports. We investigated two possible hypotheses to explain the symptoms despite low clozapine plasma levels: Hypothesis i. suggested the formation and accumulation of a reactive intermediate metabolite due to increased activity in cytochrome P450 3A5 and reduced activity in glutathione S-transferases 1, leading to myotoxicity. Hypothesis ii. proposed under-treatment with clozapine, resulting in ineffective clozapine levels, leading to a rebound effect with increased catatonic symptoms and CK levels. After considering both data sources (PGx and TDM), hypothesis ii. appeared more plausible. By comprehensively assessing all available TDM measurements and examining them in temporal correlation with the drug dose and clinical symptoms, we observed that CK levels normalized when clozapine plasma levels were raised to the therapeutic range. This was achieved through hospitalization and closely monitored clozapine intake. Therefore, we concluded that the symptoms were not an ADR due to altered clozapine metabolism but rather the result of under-treatment. Interpreting TDM and PGx results requires caution. Relying solely on isolated PGx or single TDM values can result in misinterpretation of drug reactions. We recommend considering the comprehensive patient history, including treatment, dosages, laboratory values, clinic visits, and medication adherence.

Assessing the Utility of a Genotype-Guided Tacrolimus Equation in African American Kidney Transplant Recipients: A Single Institution Retrospective Study.

Tacrolimus metabolism is heavily influenced by the CYP3A5 genotype, which varies widely among African Americans (AA). We aimed to assess the performance of a published genotype-informed tacrolimus dosing model in an independent set of adult AA kidney transplant (KTx) recipients. CYP3A5 genotypes were obtained for all AA KTx recipients (n = 232) from 2010 to 2019 who met inclusion criteria at a single transplant center in Philadelphia, Pennsylvania, USA. Medical record data were used to calculate predicted tacrolimus clearance using the published AA KTx dosing equation and two modified iterations. Observed and model-predicted trough levels were compared at 3 days, 3 months, and 6 months post-transplant. The mean prediction error at day 3 post-transplant was 3.05 ng/mL, indicating that the model tended to overpredict the tacrolimus trough. This bias improved over time to 1.36 and 0.78 ng/mL at 3 and 6 months post-transplant, respectively. Mean absolute prediction error-a marker of model precision-improved with time to 2.33 ng/mL at 6 months. Limiting genotype data in the model decreased bias and improved precision. The bias and precision of the published model improved over time and were comparable to studies in previous cohorts. The overprediction observed by the published model may represent overfitting to the initial cohort, possibly limiting generalizability.

CYP2C19 and CYP2J2 genotypes predict praziquantel plasma exposure among Ethiopian school-aged children.

Metabolism of praziquantel (PZQ), a racemic mixture and the only drug approved to treat S. mansoni infection, is mediated by genetically polymorphic enzymes. Periodic school-based mass drug administration (MDA) with PZQ is the core intervention to control schistosomiasis. However data on the impact of pharmacogenetic variation, nutrition, and infection status on plasma PZQ exposure is scarce. We investigated genetic and non-genetic factors influencing PZQ plasma concentration and its metabolic ratios (trans-4-OH-PZQ/PZQ and cis-4-OH-PZQ/PZQ). Four hundred forty-six school children aged 7-15 years from four primary schools in southern Ethiopia who received albendazole and PZQ preventive chemotherapy through MDA campaign were enrolled. Genotyping for common functional variants of CYP3A4 (*1B), CYP3A5 (*3, *6), CYP2C19 (*2, *3, *17), CYP2C9 (*2, *3), and CYP2J2*7 was performed. Plasma concentrations of PZQ, trans-4-OH-PZQ, and cis-4-OH-PZQ were quantified using UPLCMS/MS. Carriers of CYP2C19 defective variant alleles (*2 and *3) had significantly higher mean PZQ plasma concentration than CYP2C19*1/*1 or *17 carriers (p = 0.005). CYP2C19*1/*1 and CYP2C19*17 carriers had higher trans-4-OH-PZQ/PZQ and cis-4-OH-PZQ/PZQ metabolic ratios compared with CYP2C19*2 or *3 carriers (p < 0.001). CYP2J2*7 carriers had lower mean PZQ plasma concentration (p = 0.05) and higher trans-4-OH-PZQ/PZQ and cis-4-OH-PZQ/PZQ metabolic ratios. Male participants had significantly higher PZQ concentration (p = 0.006) and lower metabolic ratios (p = 0.001) than females. There was no significant effect of stunting, wasting, S. mansoni or soil-transmitted helminth infections, CYP3A4, CYP3A5, or CYP2C9 genotypes on plasma PZQ or its metabolic ratios. In conclusion, sex, CYP2C19 and CYP2J2 genotypes significantly predict PZQ plasma exposure among Ethiopian children. The impact of CYP2C19 and CYP2J2 genotypes on praziquantel treatment outcomes requires further investigation.

The Impact of ABCC2 -24C>T Gene Polymorphism on Graft Survival in Kidney Transplant Recipients.

Personalized medicine in kidney transplantation has the potential to improve outcomes and reduce complications. The aim of this study was to investigate the influence of single nucleotide polymorphisms in genes encoding metabolizing enzymes (CYP3A5) and transporters (ABCC2) on clinical outcomes (acute graft failure and/or acute tubular necrosis (ATN)) in kidney transplant recipients (KTR). This was a multicenter, retrospective cohort study where adult KTR who had undergone kidney transplantation between 2020 and 2021 and received tacrolimus-mycophenolate treatment were enrolled in the study. DNA was extracted from collected blood samples using a commercially available kit. CYP3A5*3, ABCC2 -24C>T and ABCC2 3972C>T SNP were determined by polymerase chain reaction. Of the total 39 patients included, nine (23.1%) KTR had an incidence of acute graft failure and/or ATN. A multiple logistic regression showed wildtype ABCC2 -24C>T C allele had a higher risk of developing acute graft rejection and/or ATN compared to the variant allele carriers (adjusted Odd Ratios [aOR]: 27.675, p = 0.038). Recipients who had delayed graft function (aOR: 49.214, p = 0.012) and a history of CMV infection (aOR: 18.097, p = 0.009) were at 49.2 and 18.1-times increased risk for acute graft failure and/or ATN, respectively. The large aOR was inevitable due to the small sample size and required cautious interpretation. This is the first study to determine the effect of the ABCC2 -24C>T genetic polymorphism on clinical outcomes in Malaysian KTR and forms the basis for further work on ABCC2 -24C>T effects in long-term KTR.

Drug-drug interaction between tacrolimus and caspofungin in Chinese kidney transplant patients with different CYP3A5 genotypes.

Background: The effect of drug-drug interaction between tacrolimus and caspofungin on the pharmacokinetics of tacrolimus in different CYP3A5 genotypes has not been reported in previous studies. Objectives: To investigate the effect of caspofungin on the blood concentration and dose of tacrolimus under different CYP3A5 genotypes. Design: We conducted a retrospective cohort study in The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital from January 2015 to December 2022. All kidney transplant patients were divided into the combination or non-combination group based on whether tacrolimus was combined with caspofungin or not. Patients were subdivided into CYP3A5 expressers (CYP3A5*1/*1 or CYP3A5*1/*3) and CYP3A5 non-expressers (CYP3A5*3/*3). Methods: Data from the combination and the non-combination groups were matched with propensity scores to reduce confounding by SPSS 22.0. A total of 200 kidney transplant patients receiving tacrolimus combined with caspofungin or not were enrolled in this study. Statistical analysis was conducted on the dose-corrected trough concentrations (C0/D) and dose requirements (D) of tacrolimus using independent sample two-sided t-test and nonparametric tests to investigate the impact on patients with different. Results: In this study, the C0/D values of tacrolimus were not significantly different between the combination and non-combination groups (p = 0.054). For CYP3A5 expressers, there was no significant difference in tacrolimus C0/D or D values between the combination and non-combination groups (p = 0.359; p = 0.851). In CYP3A5 nonexpressers, the C0/D values of tacrolimus were significantly lower in the combination than in the non-combination groups (p = 0.039), and the required daily dose of tacrolimus was increased by 11.11% in the combination group. Conclusion: Co-administration of caspofungin reduced tacrolimus blood levels and elevated the required daily dose of tacrolimus. In CYP3A5 non-expressers, co-administration of caspofungin had a significant effect on tacrolimus C0/D values. An approximate 10% increase in the weight-adjusted daily dose of tacrolimus in CYP3A5 non-expressers is recommended to ensure the safety of tacrolimus administration.

Differential drug interactions of caspofungin on tacrolimus in Chinese kidney transplant patients with different CYP3A5 genotypes Why was the study done? Currently, there have been studies reporting the effect of caspofungin on tacrolimus blood concentrations, but the conclusions are conflicting, and no study has focused on the effect of CYP3A5 genotypes on the drug-drug interaction. We explored a number of research questions: 1. Does caspofungin have an effect on the pharmacokinetics of the immunosuppressant tacrolimus? 2. How does CYP3A5*3, which affects tacrolimus metabolism significantly, affect tacrolimus blood concentration levels? 3. How should the dose of tacrolimus be adjusted when combined with caspofungin? What did the researchers do? By reviewing literature, we understood the problems related with the kidney transplant patients better, which led to the development of strict inclusion and exclusion criteria. The patients (from January 2015 to December 2022) were categorized into combination and non-combination groups according to whether they were co-administered with caspofungin or not. The results of the study were analyzed using SPSS 22.0. What did the researchers find? The study finally included 200 patients. We found no statistically significant differences in the dose-corrected trough concentrations (C₀/D) and dose requirements (D) of tacrolimus between the combination and non-combination groups. However, in patients with CYPA5*3/*3 genotype, tacrolimus C₀/D values were significantly lower in the combination group than in the non-combination group, and the required daily tacrolimus dose was increased. What do the findings mean? This study has found that co-administration of caspofungin in patients with CYP3A5*3/*3 genotype resulted in a significant decrease in the C₀/D value of tacrolimus, therefore, an appropriate increase in the daily dose of tacrolimus is recommended. The implication is that it is important and necessary to monitor the concentrations of tacrolimus and the CYP3A5 genotypes, and adjust the dose when combined or discontinuing with caspofungin in kidney transplant patients.

Efficacy and Toxicity of Vincristine and CYP3A5 Genetic Polymorphism in Rhabdomyosarcoma Pediatric Egyptian Patients.

BACKGROUND: Rhabdomyosarcoma (RMS) is a rare cancer that develops in soft tissue, particularly skeletal muscle tissue and occasionally hollow organs like the bladder or uterus. Vincristine (VCR) is the main therapy used in treatment of RMS, it is an alkaloid produced from vinca and it is one of the most commonly prescribed drugs in pediatric oncology for the treatment of a number of tumors. The CYP3A5 enzyme is responsible for vincristine metabolism. The effect of CYP3A5 genetic polymorphism on the efficacy and toxicity of VCR on RMS patients still needs further research. METHODS: Genotyping for CYP3A5 SNPs rs776746, rs10264272 and rs41303343 was performed using Taqman Real-Time PCR assays in a retrospective cohort study of 150 RMS pediatric patients treated with vincristine. The relationship between these genotypes and RMS survival was then examined. RESULTS: We found that patients with CYP3A5*3/*3 had the highest incidence of vincristine-induced neuropathy reaching 61.3%. Patients with CYP3A5*1/*3, CYP3A5*3/*6 and the normal metabolizers with CYP3A5*1/*1 had frequencies of 22%, 10.7%, and 4.7%. patients with the lowest frequency of 1.3% were those with the CYP3A5*1/*6 genotype. There was no correlation between the genotypes of CYP3A5*3, CYP3A5*6, CYP3A5*7, and RMS survival. Initial risk, metastasis, response, convulsions, unsteady gait and hepatotoxicity grade had a significant effect on overall survival with p<0.05. CONCLUSION: CYP3A5*1/*1 have less severe vincristine-induced neuropathy than CYP3A5 *1/*3, CYP3A5 *1/*6 and CYP3A5 *3/*3, CYP3A5 *3/*6. There is a significant influence of CYP3A5 mutation on neuropathy grade and assist of ADL as a part of neurotoxicity.

CYP3A5 unexpectedly regulates glucose metabolism through the AKT-TXNIP-GLUT1 axis in pancreatic cancer.

CYP3A5 is a cytochrome P450 (CYP) enzyme that metabolizes drugs and contributes to drug resistance in cancer. However, it remains unclear whether CYP3A5 directly influences cancer progression. In this report, we demonstrate that CYP3A5 regulates glucose metabolism in pancreatic ductal adenocarcinoma. Multi-omics analysis showed that CYP3A5 knockdown results in a decrease in various glucose-related metabolites through its effect on glucose transport. A mechanistic study revealed that CYP3A5 enriches the glucose transporter GLUT1 at the plasma membrane by restricting the translation of TXNIP, a negative regulator of GLUT1. Notably, CYP3A5-generated reactive oxygen species were proved to be responsible for attenuating the AKT-4EBP1-TXNIP signaling pathway. CYP3A5 contributes to cell migration by maintaining high glucose uptake in pancreatic cancer. Taken together, our results, for the first time, reveal a role of CYP3A5 in glucose metabolism in pancreatic ductal adenocarcinoma and identify a novel mechanism that is a potential therapeutic target.

Therapeutic efficacy of generic artemether-lumefantrine in the treatment of uncomplicated malaria in Ghana: assessing anti-malarial efficacy amidst pharmacogenetic variations.

BACKGROUND: Despite efforts made to reduce morbidity and mortality associated with malaria, especially in sub-Saharan Africa, malaria continues to be a public health concern that requires innovative efforts to reach the WHO-set zero malaria agenda. Among the innovations is the use of artemisinin-based combination therapy (ACT) that is effective against Plasmodium falciparum. Generic artemether-lumefantrine (AL) is used to treat uncomplicated malaria after appropriate diagnosis. AL is metabolized by the cytochrome P450 family of enzymes, such as CYP2B6, CYP3A4 and CYP3A5, which can be under pharmacogenetic influence. Pharmacogenetics affecting AL metabolism, significantly influence the overall anti-malarial activity leading to variable therapeutic efficacy. This study focused on generic AL drugs used in malarial treatment as prescribed at health facilities and evaluated pharmacogenomic influences on their efficacy. METHODS: Patients who have been diagnosed with malaria and confirmed through RDT and microscopy were recruited in this study. Blood samples were taken on days 1, 2, 3 and 7 for parasite count and blood levels of lumefantrine, artemisinin, desbutyl-lumefantrine (DBL), and dihydroartemisinin (DHA), the active metabolites of lumefantrine and artemether, respectively, were analysed using established methods. Pharmacogene variation analysis was undertaken using iPLEX microarray and PCR-RFLP. RESULTS: A total of 52 patients completed the study. Median parasite density from day 1 to 7 ranged from 0-2666/µL of blood, with days 3 and 7 recording 0 parasite density. Highest median plasma concentration for lumefantrine and desbutyl lumefantrine, which are the long-acting components of artemisinin-based combinations, was 4123.75 ng/mL and 35.87 ng/mL, respectively. Day 7 plasma lumefantrine concentration across all generic ACT brands was ≥ 200 ng/mL which potentially accounted for the parasitaemia profile observed. Monomorphism was observed for CYP3A4 variants, while there were observed variations in CYP2B6 and CYP3A5 alleles. Among the CYP3A5 genotypes, significant differences in genotypes and plasma concentration for DBL were seen on day 3 between 1/*1 versus *1/*6 (p = 0.002), *1/*3 versus *1/*6 (p = 0.006) and *1/*7 versus *1/*6 (p = 0.008). Day 7 plasma DBL concentrations showed a significant difference between *1/*6 and *1/*3 (p = 0.026) expressors. CONCLUSIONS: The study findings show that CYP2B6 and CYP3A5 pharmacogenetic variations may lead to higher plasma exposure of AL metabolites.

Pharmacogenomic implications of the differential distribution of CYP3A5 metabolic phenotypes among Latin American populations.

This study shows that the distribution of CYP3A5 alleles (*1, *3, *6 and *7) and genotype-predicted CYP3A5 phenotypes vary significantly across Latin American cohorts (Brazilians and the One Thousand Genomes Admixed American superpopulation), as well as among subcohorts comprising individuals with the highest proportions of Native, European or sub-Saharan African ancestry. Differences in biogeographical ancestry across the study groups are the likely explanation for these results. The differential distribution of CYP3A5 phenotypes has major pharmacogenomic implications, affecting the proportion of individuals carrying high risk CYP3A5 phenotypes for the immunosuppressant tacrolimus and the number of patients that would need to be genotyped to prevent acute rejection in kidney transplant recipients under tacrolimus treatment.

SPINK1 Overexpression Correlates with Hepatocellular Carcinoma Treatment Resistance Revealed by Single Cell RNA-Sequencing and Spatial Transcriptomics.

Low efficacy of treatments and chemoresistance are challenges in addressing refractory hepatocellular carcinoma (HCC). SPINK1, an oncogenic protein, is frequently overexpressed in many HCC cases. However, the impact of SPINK1 on HCC treatment resistance remains poorly understood. Here, we elucidate the functions of SPINK1 on HCC therapy resistance. Analysis of SPINK1 protein level reveals a correlation between elevated SPINK1 expression and unfavorable prognosis. Furthermore, intercellular variations in SPINK1 expression levels are observed. Subsequent examination of single cell RNA-sequencing data from two HCC cohorts further suggest that SPINK1-high cells exhibit heightened activity in drug metabolic pathways compared to SPINK1-low HCC cells. High SPINK1 expression is associated with reduced sensitivities to both chemotherapy drugs and targeted therapies. Moreover, spatial transcriptomics data indicate that elevated SPINK1 expression correlates with non-responsive phenotype during treatment with targeted therapy and immune checkpoint inhibitors. This is attributed to increased levels of drug metabolic regulators, especially CES2 and CYP3A5, in SPINK1-high cells. Experimental evidence further demonstrates that SPINK1 overexpression induces the expression of CES2 and CYP3A5, consequently promoting chemoresistance to sorafenib and oxaliplatin. In summary, our study unveils the predictive role of SPINK1 on HCC treatment resistance, identifying it as a potential therapeutic target for refractory HCC.

Tacrolimus Concentration/Dose Ratio: A Tool for Guiding Tacrolimus Dosage Post-renal Transplantation.

Background The calcineurin inhibitor, Tacrolimus (Tac), exhibits variable absorption and undergoes first-pass metabolism when administered orally. The narrow therapeutic window and individual variability of this immunosuppressive agent make therapeutic drug monitoring essential. We hypothesized that the Tac metabolism rate - defined as the blood concentration normalized by its daily dose (the C/D ratio) - is associated with post-renal transplant (RTx) function. Methodology A retrospective observational study was conducted including 40 RTx patients. Clinical reports from four follow-up ambulatory appointments at one, three, six, and 12 months were analyzed. Tac dose and its blood levels were used to calculate the Tac concentration/dose (C/D) ratio. Patients with a Tac C/D ratio <1.05 ng/mL x 1/mg and a C/D ratio >1.05 ng/mL x 1/mg were categorized as fast and slow metabolizers. Serum creatinine levels were compared between the two groups, and their association with the Tac C/D ratio was analyzed. Student's unpaired t-test and the Mann-Whitney U test were used to analyze the difference in the C/D ratio between the groups. Spearman correlation analysis was conducted to analyze the association of the C/D ratio with serum creatinine in both groups. A P-value of <0.05 was considered statistically significant. Results Fast metabolizers showed increased serum creatinine (P < 0.05), and the C/D ratio correlated with creatinine levels. ROC analysis used to identify fast metabolizers for the C/D ratio at three months had an area of 0.925 (P < 0.01). Conclusions The Tac C/D ratio can be used as an earlier diagnostic tool to predict the development of nephrotoxicity in RTx patients.

Characterization of CYP3A5 Selective Inhibitors for Reaction Phenotyping of Drug Candidates.

CYP3A is one of the most important classes of enzymes and is involved in the metabolism of over 70% drugs. While several selective CYP3A4 inhibitors have been identified, the search for a selective CYP3A5 inhibitor has turned out to be rather challenging. Recently, several selective CYP3A5 inhibitors have been identified through high-throughput screening of ~ 11,000 compounds and hit expansion using human recombinant enzymes. We set forth to characterize the three most selective CYP3A5 inhibitors in a more physiologically relevant system of human liver microsomes to understand if these inhibitors can be used for reaction phenotyping studies in drug discovery settings. Gomisin A and T-5 were used as selective substrate reactions for CYP3A4 and CYP3A5 to determine IC50 values of the two enzymes. The results showed that clobetasol propionate and loteprednol etabonate were potent and selective CYP3A5 reversible inhibitors with selectivity of 24-fold against CYP3A4 and 39-fold or more against the other major CYPs. The selectivity of difluprednate in HLM is much weaker than that in the recombinant enzymes due to hydrolysis of the acetate group in HLM. Based on the selectivity data, loteprednol etabonate can be utilized as an orthogonal approach, when experimental fraction metabolized of CYP3A5 is greater than 0.5, to understand CYP3A5 contribution to drug metabolism and its clinical significance. Future endeavors to identify even more selective CYP3A5 inhibitors are warranted to enable accurate determination of CYP3A5 contribution to metabolism versus CYP3A4.