CYP3A5 Genotype Research Articles

Comparison of Tacrolimus Intra-Patient Variability during 6-12 Months after Kidney Transplantation between CYP3A5 Expressers and Nonexpressers.

A high intra-patient variability (IPV) of tacrolimus exposure is associated with poor long-term kidney transplantation outcomes. To assess the influence of cytochrome P450 (CYP) 3A5 genetic polymorphisms on tacrolimus IPV, 188 clinically stable kidney transplant recipients, who had received an immediate-release tacrolimus-based immunosuppressive regimen, were enrolled in this retrospective cohort study. Genotyping of CYP3A5*3 (rs776746) was performed and 110 (58.5%) were identified as CYP3A5 expressers and 78 (41.5%) as nonexpressers. Whole blood tacrolimus concentrations were analyzed by chemiluminescent microparticle immunoassay. Dose-adjusted trough tacrolimus concentrations (C0/D) measured at months 6, 9, and 12 were used to determine IPV. There were no significant differences in the IPV estimated by the coefficient of variation, the IPV calculated by mean absolute deviation method, and the proportions of recipients with the IPV estimated by the coefficient of variation of 30% or more between CYP3A5 expressers and nonexpressers (p = 0.613, 0.686, and 0.954, respectively). Tacrolimus C0/D in CYP3A5 expressers was approximately half of those in nonexpressers, overall (p < 0.001). In both CYP3A5 expressers and nonexpressers, tacrolimus C0/D increased gradually from month 6 to month 12 (p = 0.021). There was no evidence that the CYP3A5 polymorphisms significantly influence tacrolimus IPV during the 6 to 12 months after kidney transplantation.

Impact of Genetic Variants in the Nicotine Metabolism Pathway on Nicotine Metabolite Levels in Smokers.

Nicotine metabolism is a major factor in nicotine dependence, with approximately 70% to 80% of nicotine metabolized to cotinine in Caucasians. Cotinine formation is catalyzed primarily by CYP2A6, which also converts cotinine to trans-3'-hydroxycotinine (3HC). The goal of the present study was to examine the effects of CYP2A6 deficiency on nicotine metabolism profiles in vivo and the importance of genetic variants in nicotine-metabolizing enzyme genes on urinary nicotine metabolites levels. Urine samples from 722 smokers who participated in the Singapore Chinese Health Study were analyzed using UPLC-MS/MS to detect nicotine and eight of its urinary metabolites, and a total of 58 variants in 12 genes involved in nicotine metabolism were investigated in 475 of these subjects with informative genotyping data. Urine samples stratified by the ratio of 3HC/cotinine exhibited a 7-fold increase in nicotine-N'-oxide, a 6-fold increase in nicotine-Glucuronide (Gluc), and a 5-fold decrease in 3HC-Gluc when comparing the lower versus upper 3HC/cotinine ventiles. Significant (P < 0.0001) associations were observed between functional metabolizing enzyme genotypes and levels of various urinary nicotine metabolites, including CYP2A6 genotype and levels of nicotine, nicotine-Gluc, nicotine-N'-oxide and 3HC, UGT2B10 genotype and levels of cotinine, nicotine-Gluc and cotinine-Gluc, UGT2B17 genotype and levels of 3HC-Gluc, FMO3 genotype and levels of nicotine-N'-oxide, and CYP2B6 genotype and levels of nicotine-N'-oxide and 4-hydroxy-4-(3-pyridyl)-butanoic acid. These data suggest that several pathways are important in nicotine metabolism. Genotype differences in several nicotine-metabolizing enzyme pathways may potentially lead to differences in nicotine dependence and smoking behavior and cessation.

Model-Based Tacrolimus Follow-up Dosing in Adult Renal Transplant Recipients: A Simulation Trial.

Initial algorithm-based dosing appears to be effective in predicting tacrolimus dose requirement. However, achieving and maintaining the target concentrations is challenging. Model-based follow-up dosing, which considers patient characteristics and pharmacological data, may further personalize treatment. This study investigated whether model-based follow-up dosing could lead to more accurate tacrolimus exposure than standard therapeutic drug monitoring (TDM) in kidney transplant recipients after an initial algorithm-based dose. This simulation trial included patients from a prospective trial that received an algorithm-based tacrolimus starting dose followed by TDM. For every measured tacrolimus predose concentration (C 0,obs ), model-based dosing advice was simulated using the InsightRX software. Based on previous tacrolimus doses and C 0 , age, body surface area, CYP3A4 and CYP3A5 genotypes, hematocrit, albumin, and creatinine, the optimal next dose, and corresponding tacrolimus concentration (C 0,pred ) were predicted. Of 190 tacrolimus C 0 values measured in 59 patients, 121 (63.7%; 95% CI 56.8-70.5) C 0,obs were within the therapeutic range (7.5-12.5 ng/mL) versus 126 (66.3%, 95% CI 59.6-73.0) for C 0,pred ( P = 0.89). The median absolute difference between the tacrolimus C 0 and the target tacrolimus concentration (10.0 ng/mL) was 1.9 ng/mL for C 0,obs versus 1.6 ng/mL for C 0,pred . In a historical cohort of 114 kidney transplant recipients who received a body weight-based starting dose followed by TDM, 172 of 335 tacrolimus C 0 (51.3%) were within the therapeutic range (10.0-15.0 ng/mL). The combination of an algorithm-based tacrolimus starting dose with model-based follow-up dosing has the potential to minimize under- and overexposure to tacrolimus in the early posttransplant phase, although the additional effect of model-based follow-up dosing on initial algorithm-based dosing seems small.

The effects of CYP1A2 and ADORA2A genotypes association with acute caffeine intake on physiological effects and performance: A systematic review

Introduction: This systematic review aims to examine the effects of the CYP1A2 −163C&gt;A and ADORA2A 1976T&gt;C polymorphism on physiological effects and performance relative to caffeine consumption. Material and Methods: In this study, electronic databases including PubMed, Web of Science Core Collection, Korean Journal Database, Russian Science Citation Index, SciELO Citation Index, Scopus, ScienceDirect, ProQuest Dissertations &amp; Thesis Global and EBSCO were searched. Results: The results highlight that individuals with the TT or CT/CC genotype can have differences in caffeine consumption, and C carriers may have increases in the maximum oxygen uptake (VO2max). The AA or AC/CC genotypes can have different caffeine consumption and VO2max. In four studies, TT or CT/CC either in AA or CC genotype had different physiological effects. Regardless of the amount of caffeine (3 mg/kg-5 mg/kg), Carriers of the C allele in the genotype ADORA2A gene have higher sports performance. Six studies revealed a significant correlation between the AA genotype and performance following caffeine intake. Conclusions: Genotype variations in ADORA2A and CYP1A2 may modulate the ergogenic effects of caffeine, but some physiological effects can occur for different genotypes.

Prediction of pyrotinib exposure based on physiologically-based pharmacokinetic model and endogenous biomarker.

Pyrotinib, a novel irreversible epidermal growth factor receptor dual tyrosine kinase inhibitor, is mainly (about 90%) eliminated through cytochrome P450 (CYP) 3A mediated metabolism in vivo. Meanwhile, genotype is a key factor affecting pyrotinib clearance and 4β-hydroxycholesterol is an endogenous biomarker of CYP3A activity that can indirectly reflect the possible pyrotinib exposure. Thus, it is necessary to evaluate the clinical drug-drug interactions (DDI) between CYP3A perpetrators and pyrotinib, understand potential exposure in specific populations including liver impairment and geriatric populations, and explore the possible relationships among pyrotinib exposure, genotypes and endogenous biomarker. Physiologically-based pharmacokinetic (PBPK) model can be used to replace prospective DDI studies and evaluate external and internal factors that may influence system exposure. Herein, a basic PBPK model was firstly developed to evaluate the potential risk of pyrotinib coadministration with strong inhibitor and guide the clinical trial design. Subsequently, the mechanistic PBPK model was established and used to quantitatively estimate the potential DDI risk for other CYP3A modulators, understand the potential exposure of specific populations, including liver impairment and geriatric populations. Meanwhile, the possible relationships among pyrotinib exposure, genotypes and endogenous biomarker were explored. With the help of PBPK model, the DDI clinical trial of pyrotinib coadministration with strong inhibitor has been successfully completed, some DDI clinical trials may be waived based on the predicted results and clinical trials in specific populations can be reasonably designed. Moreover, the mutant genotypes of CYP3A4*18A and CYP3A5*3 were likely to have a limited influence on pyrotinib clearance, and the genotype-independent linear correlation coefficient between endogenous biomarker and system exposure was larger than 0.6. Therefore, based on the reliable predicted results and the linear correlations between pyrotinib exposure and endogenous biomarker, dosage adjustment of pyrotinib can be designed for clinical practice.

Prediction of tacrolimus and Wuzhi tablet pharmacokinetic interaction magnitude in renal transplant recipients.

Wuzhi tablets are a dose-sparing agent for tacrolimus (TAC) in China and increase the bioavailability of TAC. The current study aimed to evaluate the pharmacokinetic interaction magnitude of Wuzhi and TAC and explore the potential determinants of this interaction. This study performed a retrospective, self-controlled study of 138 renal transplant recipients who were co-administered TAC and Wuzhi. The trough concentration (C0) of TAC at baseline and 3, 7, 14 and 21 days after Wuzhi co-therapy initiation was measured, and the CYP3A5 polymorphism was genotyped. The corresponding clinical factors were recorded. The ratio of dose-adjusted C0 (C0/D) post- and pre-combination therapy (ΔC0/D) indicates the interaction magnitude. Univariate and multivariate analyses were used to identify determinants and establish the prediction model. ΔC0/D reached a steady state within 14 days. The geometrical mean ΔC0/D was 2.91 (range 1.02-9.49, IQR 2.13-3.80). ΔC0/D was blunted in CYP3A5 expressers (estimated effect: -39.8%, P=.001) and affected by hematocrit (Hct) (+24.0% per 10% increase, P=.005) and baseline C0/D (-31.9% per 1ng·ml-1 ·mg-1 increase, P<.001). The prediction model was ΔC0/D=.319baseline C0/D × 1.398CYP3A5 (expressers=0/non-expressers=1) × 1.024Hct × 1.744, and it explained 28.1% of the variability. Our study is the first attempt to date to give an assessment of the magnitude of pharmacokinetic interaction between TAC and Wuzhi in a cohort of renal transplant recipients, and CYP3A5 genotypes, baseline C0/D and Hct were identified as determinants of this interaction.

CYP2A6 gene polymorphism and severity of coronary atherosclerosis in Indonesian male smokers: A pilot study.

Nicotine is a toxic alkaloid known to be responsible for the addictive feature of cigarettes. CYP2A6 genetic polymorphism among individuals was suspected to explain the relationship between cigarette smoking and related diseases. CYP2A6 works to slow nicotine metabolism and thus maintain a more prolonged nicotine concentration and increase nicotine exposure to the blood. We aimed to investigate the correlation between the CYP2A6 gene with the severity of coronary atherosclerosis. This cross-sectional study was conducted from April to July 2010 in Makassar Cardiac Centre, Dr Wahidin Sudirohusodo Hospital, Indonesia. Sixty-four male active smokers at the age of ≥45 years, diagnosed with coronary artery disease (CAD), were recruited and asked to smoke the usual number of cigarettes in the last 1 month prior to blood collection for CYP2A6 genotyping. Spearman correlation was performed to analyze the association between the allele variants and coronary stenosis degree, adjusted for CAD risk factors. Furthermore, we estimated the risk ratio to quantify the correlation. Of the 64 male smokers with CAD, the mean duration of smoking was 36.9 ± 8.6 years, and 49 (76.6%) were heavy smokers with >20 cigarettes per day. All 128 alleles were observed. Our results showed that all participants with CYP2A6 variants had a significant correlation with severe coronary artery stenosis (P = .006). Thus, this study suggests that the mutant CYP2A6 gene allele significantly increased the risk of having severe coronary stenosis 1.2 times higher compared to the wild type. This pilot study showed that CYP2A6 gene has an influential role in atherosclerotic development in male smokers. However, our findings should be confirmed with further more extensive studies.

The pharmacokinetic study of tacrolimus and Wuzhi capsule in Chinese liver transplant patients.

Objectives: Wuzhi Capsule (WZC) is often administrated with tacrolimus in liver transplant patients to reduce the toxicity of tacrolimus and relieve the financial burden of patients. We aimed to investigate the interaction between Wuzhi Capsule (WZC) and tacrolimus in liver transplant patients. Methods: We applied the LC-MS/MS analytical method previously established to study the pharmacokinetic characteristics of the analytes in 15 liver transplant patients. CYP3A5 genotypes were determined in 15 donors and recipients, and they were categorized into CYP3A5 expressers and non-expressers respectively. Results: The influences of CYP3A5 in donors and recipients on the pharmacokinetics of tacrolimus with or without WZC were also studied. We found that 1) WZC could influence the metabolism of tacrolimus, which shortened the Tmax of tacrolimus and decreased V/F and CL/F. 2) Moreover, our results showed that, in donors, the CL/F of tacrolimus were significantly lower in CYP3A5 (CYP3A5*1) expressers (decreased from 24.421 to 12.864) and non-expressers (decreased from 23.532 to 11.822) when co-administration with WZC. For recipients, the decreased trend of CL/F of tacrolimus was seen when co-administrated with WZC by 15.376 and 12.243 in CYP3A5 expressers and non-expressers, respectively. Conclusion: In this study, the pharmacokinetics effects of WZC on tacrolimus were identified. The co-administration of WZC can increase the tacrolimus blood concentration in Chinese liver transplant patients in clinical practice.

Impact of CYP3A5 Status on the Clinical and Financial Outcomes Among African American Kidney Transplant Recipients.

Background.Pharmacogenetic profiling of transplant recipients demonstrates that the marked variation in the metabolism of immunosuppressive medications, particularly tacrolimus, is related to genetic variants. Patients of African ancestry are less likely to carry loss-of-function (LoF) variants in the CYP3A5 gene and therefore retain a rapid metabolism phenotype and higher clearance of tacrolimus. Patients with this rapid metabolism typically require higher dosing to achieve therapeutic trough concentrations. This study aims to further characterize the impact of CYP3A5 genotype on clinical outcomes and financial expenditure.Methods.The CYP3A5 phenotype status was identified in 438 adult kidney transplant (KTx) recipients (96% were African American) using 3 LoF alleles (CYP3A5*3, *6 or *7). Individuals were categorized as rapid metabolism phenotype without LoF alleles‚ intermediate phenotype for 1 LoF allele‚ and slow phenotype for 2 LoF alleles. KTx outcomes (patient/kidney survival and Medicare spending) were determined using linked transplant registry and claims data.Results.Among the cohort, 23% had a rapid, 47% intermediate, and 30% a slow metabolism phenotype based on genotype. At 3 y, the rate of death censored graft failure and all cause graft failure was highest in the rapid metabolism phenotype and lowest in the intermediate metabolism phenotype group. First-year Medicare reimbursement differed significantly by genotype (rapid: $79 535, intermediate: $72 796, slow: $79 346, P = 0.03). After adjustment for donor and recipient characteristics, care for patients with intermediate metabolism was $4790 less expensive (P = 0.003).Conclusions.Pharmacogenomic assessment of African American KTx recipients may be useful to guide therapy when as CYP3A5 functional variants appear to be associated with differential outcome and spending after transplant.

Tacrolimus Concentration Is Effectively Predicted Using Combined Clinical and Genetic Factors in the Perioperative Period of Kidney Transplantation and Associated with Acute Rejection.

Background Tacrolimus has unpredictable pharmacokinetic (PK) characteristics, which are partially attributed to CYP3A5 polymorphism. The potential effects of clinical factors in the postoperative period of transplantation on tacrolimus PK and those of early tacrolimus PK variability on clinical outcomes are yet to be clarified. Methods We examined the genetic and clinical factors affecting early tacrolimus PK variability in 256 kidney transplant recipients. The relationships among tacrolimus exposure, graft function delay (DGF), and acute rejection (AR) were further explored. Findings. The CYP3A5 genotype were strongly associated with tacrolimus concentration/dose ratio (C0/D). Additionally, ABCB1 (rs1045642 and rs2032582) and ABCC2 (rs3740066) were found to have potential independent effects on early tacrolimus C0/D in multivariate analysis. Red blood counts and albumin level were the most significant clinical factors associated with tacrolimus C0/D. Wuzhi capsule also exerted an effect on tacrolimus PK. A model combined with pharmacogenetic and clinical factors explained 43.4% tacrolimus PK variability compared with 16.3% on the basis of CYP3A5 genotype only. Notably, increasing tacrolimus concentrations in the early postoperative stage were associated with AR, but not DGF. Conclusions Combined analysis of genotype and specific clinical factors is important for the formulation of precise tacrolimus dose regimens in the early stage after kidney transplantation.

The effect of rs776746 polymorphism in the &lt;i&gt;CYP3A5&lt;/i&gt; gene on heart rate when using bisoprolol in patients with acute coronary syndrome

Aim. The aim of this work was to study the occurrence of the rs776746 allelic variant of the CYP3A5 gene and its effect on heart rate (HR) when using bisoprolol in patients hospitalized with acute coronary syndrome (ACS).Materials and methods. The study included patients with ACS who were prescribed bisoprolol for clinical indications. All patients underwent molecular genetic testing. In order to evaluate the effectiveness of the therapy with bisoprolol, all patients underwent Holter electrocardiogram (ECG) monitoting on days 10, the following parameters were assessed: minimum, average, maximum heart rate and heart rate during an exercise test. The stress test was performed as a ladder test.Results. The study involved 97 patients (63,5±10,5 years), including 60 men and 37 women. The frequency of occurrence of the desired alleles of the CYP3A5 gene was: CYP3A5*3 - 93%, and CYP3A5*1 - 7%, which corresponds to its prevalence in the European population. 84 carriers of the CYP3A5*3*3 genotype (87%), 12 heterozygous carriers of the *1 allele (12%) and one patient with the *1*1 genotype (1%) were identified. In order to search for differences in the effects of bisoprolol depending on the genetically predetermined activity of CYP3A5, we divided the general group of patients into two subgroups: subgroup 1 (CYP3A5*3*3), represented by carriers of the genotype associated with the synthesis of the inactive form of CYP3A5, and subgroup 2 (CYP3A5*1*3 and CYP3A5*1*1), represented by carriers of at least one allele encoding the synthesis of a fully functional protein CYP3A5, coupled with an increased metabolic rate. Patients did not differ in clinical and demographic characteristics. By the time of daily ECG monitoring, both groups reached comparable heart rate values. In carriers of at least one CYP3A5*1 allele (n = 13), associated with an increased metabolic rate, the daily dose of bisoprolol on the 10th day of hospitalization was significantly higher (p &lt;0.05). The only carrier of the homozygous CYP3A5 *1*1 variant receives bisoprolol at a daily dose of 10 mg. Taking into account the close to significant differences in glomerular filtration rate (GFR) in patients in the groups with the studied genetic variants, and the known eliminating role of the kidneys for bisoprolol, a linear regression model was built with the inclusion of factors that could affect the dose of bisoprolol: GFR, functional class of chronic heart failure, gender, age, number of simultaneously assigned CYP3A5 substrates. Of the parameters listed, only the CYP3A5 genotype significantly predicted the dose of bisoprolol (F=8.5; p&lt;0.005; R2=0.096).Conclusion. In this study, it was demonstrated for the first time that patients with different genetic variants of CYP3A5, in particular with respect to the rs776746 polymorphism, may differ in individual requirements for the dose of bisoprolol.

245.9: Influence of Tacrolimus CYP3A5 Polymorphisms on the Doselevel Response After Pediatric Kidney Transplantation

Background: Tacrolimus exhibits wide inter and intra-patient variability. CYP3A5 tacrolimus polymorphisms predict its metabolization. We aim to identify the influence of polymorphisms on the pharmacological parameters. The present report is part of the exploratory data analysis of a pediatric trial that used the initial tacrolimus dose according to the CYP3A5 genotype in kidney transplant recipients. Methods: We performed an exploratory data analysis of pharmacological parameters from a single-center, non-randomized, open-label clinical trial in children from 0-to 18 years of age who received a kidney transplant at the Hospital Infantil de México, Federico Gómez from January 2013 to December 2018. All children were genotyped before transplantation and assigned to one of two groups: the Genotype-guided group, which initial dose was according to the CYP3A5 polymorphisms and the Conventional-dose group (see abstract AID-1780), with further dose adjustments on the decision of the clinicians. We followed them for six weeks and recorded tacrolimus dose received, trough level achieved, deltas of dose and trough levels between time points (weekly). Results: We included 81 subjects; 40 received the genotype-guided dose, the mean age at transplantation was 13.3 y/o, 51.8% were female. After six weeks of transplantation, linear regressions showed no linear associations between tacrolimus dose and levels in the genotype-guided dose group (r2=0.0003, p=0.78) or the conventional-dose group (r2=0.0008, p=67). However, there were linear associations between the delta-dose and delta-levels in the genotype-guided dose group (r2=0.138, p=<0.0001) and conventional-dose group (r2=0.081, p=<0.0001). The subgroup analysis by genotype showed that AG1*3 polymorphism had a linear association between the tacrolimus delta-dose and delta-level (r2=0.168, p=<0.001). Furthermore, It reached statistical significance in the tacrolimus dose vs level analysis (r2=0.0308, p= 0.02). The GG3*3 polymorphism showed an association only in the delta-dose vs delta-level analysis (r2=0.057, p=<0.001), while the AA1*1 genotype did not show any linear associations between tacrolimus dose vs trough level or deltas (r2=0.006, p=0.64 and r2=0.108, p=0.08 respectively) (Figure). Conclusion: The tacrolimus delta-dose and delta-level across the different polymorphisms translate the clinician’s decisions. The trough levels’ response to dose adjustments might be guided by the CYP3A5 genotypes, specifically the AG1*3. Further studies are needed to estimate more accurate associations.

POS-075 ASSOCIATION OF CYP3A5 POLYMORPHISM WITH INFECTIONS IN KIDNEY TRANSPLANT RECIPIENTS

Kidney transplant recipients who are non-expressors (CYP3A5*3/*3 genotype) are known to have increased dose-adjusted trough concentrations of tacrolimus as compared with those who are CYP3A5 expressors (CYP3A5*1/*1 and CYP3A5*1/*3 genotypes), possibly delaying achievement of target concentrations. Also, tacrolimus increases the exposure of mycophenolate mofetil by 30%. Both these factors in patients who are non-expressors can increase the risk of infections. However, there is lack of data corelating CYP3A5 polymorphism with infections post-kidney transplant. We retrospectively evaluated 181 out of 260 kidney transplant recipients who were at regular follow up at the transplant clinic of a tertiary referral center in western India from 2018 to 2021. Recipients on tacrolimus for at least 3 months post-transplant were eligible for evaluation. They were categorized into non-expressors (CYP3A5*3/*3) and expressors (CYP3A5*1/*1 and CYP3A5*1/*3 genotype). The infectious burden was evaluated by the incidence of total infections and further classified according to etiologies such as bacterial, viral, parasitic, fungal and mycobacterial and specific system patterns such as diarrhea, urinary tract infections, tropical illnesses, infections of the skin, soft tissue and musculoskeletal system. The incidence of non-infectious diarrhea was evaluated as a measure of increased MMF exposure. Multivariate logistic regression was performed to evaluate the impact of genotype on the risk of infections. Out of 181 recipients, 103 (56.9%) were non-expressors and 78 (43%) were expressors. Mean (SD) age was 35±10 years with 128 (70.7%) being males. Their mean (SD) eGFR at enrollment was 57.72± 23.15 ml/min/1.73m2. Higher number of non-expressors received antibody induction at the time of transplant but this difference was not statistically significant (52.4% vs 42.3%, p= 0.177). New onset diabetes after transplant observed in the non-expressor group was higher, but did not reach statistical significance (37.2% vs 29.1%, p= 0.252). Overall incidence of infections was similar in both groups (85.4% vs 89.7%, p = 0.389), however tuberculosis was significantly more common in non-expressors (16.7 % vs 6.8%, p= 0.036). This association remained significant (p= 0.043) after controlling for factors such as history of tuberculosis before transplant, antibody induction, living vs deceased donor, triple or dual immunosuppression at time of transplant, and anti-rejection therapy. Infectious diarrhea, fungal infections, parasitic infections, were higher in non-expressors, but this difference was not statistically significant. Hospitalization for infectious diarrhea was significantly higher in non-expressors (20.5% vs 7.8%, p= 0.012). Non-infectious diarrhea attributed to MMF was significantly higher in non-expressors (32.1% vs 19.2%, p= 0.035). Viral infections were higher in non-expressors but were statistically insignificant (51.3% vs 40.8%, p= 0.160). Mortality due to infectious causes was higher in non-expressors but was not statistically significant (6.4% vs 3.9%, p= 0.439). Non-expressor CYP3A5 genotype in kidney transplant recipients is associated with a significant burden of infectious complications and a higher incidence of MMF induced diarrhea. A genotype-based approach may help individualizing dosing of tacrolimus in this population.

Compare the performance of multiple machine learning models in predicting tacrolimus concentration for infant patients with living donor liver transplantation.

This study aims to establish multiple ML models and compare their performance in predicting tacrolimus concentration for infant patients who received LDLT within 3 months after transplantation. Retrospectively collected basic information and relevant biochemical indicators of included infant patients. CMIA was used to determine tacrolimus C0 . PCR was used to determine the donors' and recipients' CYP3A5 genotypes. Multivariate stepwise regression analysis and stepwise elimination covariates were used for covariates selection. Thirteen machine learning algorithms were applied for the development of prediction models. APE, the ratio of the APE ≤3ng ml-1 and ideal rate (the proportion of the predicted value with a relative error of 30% or less) were used to evaluate the predictive performance of the model. A total of 163 infant patients were included in this study. In the case of the optimal combination of covariates, the Ridge model had the lowest APE, 2.01 (0.85, 3.35 ng ml-1 ). The highest ratio of the APE ≤3ng ml-1 was the LAR model (71.77%). And the Ridge model showed the highest ideal rate (55.05%). For the Ridge model, GRWR was the most important predictor. Compared with other ML models, the Ridge model had good predictive performance and potential clinical application.

The effect of the very low dosage diltiazem on tacrolimus exposure very early after kidney transplantation: a randomized controlled trial

The objective of this study was to assess the effect of the very low dosage of diltiazem on tacrolimus exposure during the first week post-kidney transplantation, among cytochrome P450 (CYP) 3A5 expressers who did not receive diltiazem (EXplb), CYP3A5 expressers who received the very low dose diltiazem (EXdtz), CYP3A5 nonexpressers who did not receive diltiazem (NEplb), and CYP3A5 nonexpressers who received the very low dose diltiazem (NEdtz). Forty kidney recipients who receive tacrolimus-based immunosuppressive regimen were randomly assigned, with stratification on the CYP3A5 genotypes, to receive either diltiazem 30 mg every 12 h or a matched placebo. The observed median dose-adjusted area under the 12-h curve of tacrolimus concentration (AUC/D) at day 7 post-transplantation was lowest in the EXplb group followed by EXdtz, NEplb, and NEdtz at 34.9, 43.6, 49.4, and 71.1 ng*h/mL per mg, respectively. A Kruskal–Wallis test showed a significant difference in the mean ranks of AUC/D among groups. Significant differences between EXplb and NEplb, and between EXplb and NEdtz were demonstrated, whereas no sufficient evidence of significant differences was detected between the other pairs. In conclusion, coadministration of diltiazem 30 mg twice daily may be advantageous for increasing tacrolimus exposure early after kidney transplantation among CYP3A5 expressers.

Tacrolimus induces a pro-fibrotic response in donor-derived human proximal tubule cells dependent on common variants of the CYP3A5 and ABCB1 genes.

Common genetic variants of the enzymes and efflux pump involved in tacrolimus disposition have been associated with calcineurin inhibitor nephrotoxicity, but their importance is unclear because of the multifactorial background of renal fibrosis. This study explores the pro-fibrotic response of tacrolimus exposure in relation to the differential capacity for tacrolimus metabolism in proximal tubule cells (PTCs) with a variable (pharmaco)genetic background. PTCs were obtained from protocol allograft biopsies with different combinations of CYP3A5 and ABCB1 variants and were incubated with tacrolimus within the concentration range found in vivo. Gene and protein expression, CYP3A5 and P-glycoprotein function, and tacrolimus metabolites were measured in PTC. Connective tissue growth factor (CTGF) expression was assessed in protocol biopsies of kidney allograft recipients. PTCs produce CTGF in response to escalating tacrolimus exposure, which is approximately 2-fold higher in cells with the CYP3A5*1 and ABCB1 TT combination in vitro. Increasing tacrolimus exposure results in relative higher generation of the main tacrolimus metabolite {13-O-desmethyl tacrolimus [M1]} in cells with this same genetic background. Protocol biopsies show a larger increase in in vivo CTGF tissue expression over time in TT vs. CC/CT but was not affected by the CYP3A5 genotype. Tacrolimus exposure induces a pro-fibrotic response in a PTC model in function of the donor pharmacogenetic background associated with tacrolimus metabolism. This finding provides a mechanistic insight into the nephrotoxicity associated with tacrolimus treatment and offers opportunities for a tailored immunosuppressive treatment.

Effects of gene polymorphisms of CYP1A1, CYP1B1, EPHX1, NQO1, and NAT2 on urinary 1-nitropyrene metabolite concentrations

Nitropyrene (1-NP) is a specific indicator of exposure to diesel exhaust and is partly metabolized to 1-aminopyrene (1-AP) and N-acetyl-1-aminopyrene (1-NAAP), which are excreted in urine. This study was conducted to evaluate the effects of gene polymorphisms of metabolic enzymes for 1-NP on the urinary concentrations of 1-AP and 1-NAAP. The study participants were 70 South Koreans who were occupationally or environmentally exposed to diesel exhaust. To evaluate 1-NP exposure levels, we sampled airborne particulate matters with a personal air sampler and measured urinary 1-AP and 1-NAAP concentrations. The genetic polymorphisms of the 1-NP metabolic enzymes (CYP1A1, CYP1B1, EPHX1, NQO1, and NAT2) were determined by direct sequencing. The mean 1-NP exposure level was 20.40 pg/m3, and the mean urinary concentrations of 1-AP and 1-NAAP were 0.074 nM and 0.213 nM, respectively. The correlation coefficient between the 1-NP exposure level and urinary 1-AP concentrations was 0.0138 and that between the 1-NP exposure level and urinary 1-NAAP concentrations was 0.1493, and neither correlation coefficient was statistically significant. The correlation coefficient between the 1-NP exposure level and urinary 1-AP concentrations showed statistically significant differences according to the CYP1A1 and CYP1B1 genotypes, and that between the 1-NP exposure level and urinary 1-NAAP concentrations was significantly different according to the CYP1A1, CYP1B1, and NAT2 genotypes. The urinary concentration of 1-NAAP is a better biomarker for exposure to 1-NP or DEPs because the former is higher, easier to measure, and more strongly correlated with 1-NP exposure levels than that of 1-AP. The relationship between 1-NP exposure and urinary 1-AP or 1-NAAP concentration depends on the single nucleotide polymorphism types of CYP1A1, CYP1B1, NQO1, and NAT2.

The Impact of CYP3A5, CYP1A1, GSTM1, GSTT1, GSTP1 and TPMT Gene Polymorphisms on the Risk of Chronic Myeloid Leukemia

Polymorphisms in the genes encoding drug metabolising enzymes (DME) cause inter-individual variations in metabolising exogenous and endogenous substances, which has been related to the risk of various diseases. The present study was conducted to investigate the association of CYP1A1, GSTM1, GSTT1, GSTP1 and CYP3A5 and TPMT gene polymorphisms with susceptibility to chronic myeloid leukemia (CML). 89 samples of CML patients and 135 control samples were included in this study. Genotyping of CYP1A1, GSTM1, GSTT1, GSTP1 and CYP3A5 and TPMT gene polymorphisms was performed by a Polymerase chain reaction-Restriction fragment length polymorphism (PCR-RFLP). The frequency of GSTM1 null genotype was found to be significantly higher among chronic myeloid leukemia (CML) patients vs controls (39% vs 18.5%, respectively) with a 2.85-fold increased risk for CML. The frequency of GSTT1 null was found to be significantly lower in CML patients vs controls (26% vs 40.7%). Under the dominant inheritance model, GSTP1 gene polymorphism was significantly associated with reduced risk of CML. Moreover, CYP3A5 * 6 and TPMT * 2 alleles were absent among CML patients and the control group. GSTM1 null genotype was found to be associated with an increased risk of CML whereas TPMT * 2 and CYP3A5 * 6 alleles were absent in the population of Punjab.

Population Pharmacokinetics and Initial Dosage Optimization of Tacrolimus in Pediatric Hematopoietic Stem Cell Transplant Patients.

Background: There is a substantial lack of tacrolimus pharmacokinetic information in pediatric hematopoietic stem cell transplant (HSCT) patients. This study aimed to develop population pharmacokinetics (PopPK) of tacrolimus in pediatric HSCT patients and to devise model-guided dosage regimens. Methods: A retrospective analysis was performed on 86 pediatric HSCT patients who received tacrolimus intravenously or orally. A total of 578 tacrolimus trough concentrations (C0) were available for pharmacokinetic analysis using a non-linear mixed-effects modeling method. Demographic and clinical data were included and assessed as covariates via the stepwise method. Bayesian estimators were used to devise pediatric dosage regimens that targeted C0 of 5–15 ng mL−1. Results: A one-compartment model with first-order absorption adequately described the tacrolimus pharmacokinetics. Clearance (CL), volume of distribution (V), and typical bioavailability (F) in this study were estimated to be 2.42 L h−1 (10.84%), 79.6 L (16.51%), and 19% (13.01%), respectively. Body weight, hematocrit, post-transplantation days, and caspofungin and azoles concomitant therapy were considered significant covariates for tacrolimus CL. Hematocrit had a significant impact on the V of tacrolimus. In the subgroup cohort of children (n = 24) with CYP3A5 genotype, the clearance was 1.38-fold higher in CYP3A5 expressers than in non-expressers. Simulation indicated that the initial dosage optimation of tacrolimus for intravenous and oral administration was recommended as 0.025 and 0.1 mg kg−1 d−1 (q12h), respectively. Conclusion: A PopPK model for tacrolimus in pediatric HSCT patients was developed, showing good predictive performance. Model-devised dosage regimens with trough tacrolimus concentrations provide a practical strategy for achieving the therapeutic range.

Association of CYP2A6 Genetic Polymorphism and Lung Cancer in Female Never Smokers

Background: The major significant factor that affected lung cancer development among female passive smokers is environmental tobacco smoke. Nicotine can be found in a never smoker population, such as a child whose father is a smoker. Lung carcinogenesis in never smoker populations is affected by nicotine metabolism by CYP2A6 gene, which encodes the main nicotine metabolizing-enzyme. The aim of this study was to assess the genetic polymorphism of CYP2A6 and its association with secondhand smokers among females who have suffered from lung cancer in North Sumatra population.Materials and methods: This study was a case-control study, composed of 53 case subjects and 46 control subjects that were involved through a purposive sampling technique from two hospitals in Medan. PCR-RFLP was used for the examination of CYP2A6 gene to determine the genotype. The data were analyzed with conditional logistic regression test using Epi Info 7.0 software.Results: The most common genotype of CYP2A6 detected in this study was *1B/*1B (40.4%), while *1B allele had the highest prevalence (55.5%). There was no significant association between CYP2A6 genotype (p-value=0.61) or alleles (p-value=0.25) and the incidence of lung cancer.Conclusion: There was no association between CYP2A6 polymorphism and the incidence of lung cancer in secondhand smoker females.Keywords: CYP2A6, PCR-RFLP, female secondhand smokers, lung cancer