CYP3A4 Variants Research Articles

Synergistic Effect of Cytochrome P450 Family 3 Subfamily A Member 5 (CYP3A5) Genetic Variants in Tacrolimus Dose Determination in Indian Renal Transplant Patients.

Tacrolimus (TAC) has a narrow therapeutic index and shows interindividual variabilities in its blood concentration. Although guidelines recommend a genetic variant (rs776746) to determine the optimized TAC dose, discrepancies in accuracy have been noted. Therefore, studying other variants of CYP3A5 may improve the accuracy of the TAC dose. Clinical exome sequencing (CES) was performed in 219 renal transplant patients. The SNPs of CYP3A5 covered by CES were recorded. The TAC blood trough concentration/dose (C 0/D) was calculated on day 7 and months 1, 3, 6, and 12 of post-transplantation, and association with CYP3A5 genotypes was studied. Further, biopsy-proven rejection and pathological events were analyzed for their association with CYP3A5 genotypes. Out of 35 variants of CYP3A5 covered in CES, rs776746, rs15524, rs4646449, and rs464645 were significantly associated with the TAC C 0/D on day 7 and months 1, 3, and 6. Further analysis showed that the slow-metabolizing genotypes of all four SNPs synergistically associated with the TAC C 0/D on day 7 and months 1, 3, 6, and 12. The "CC" genotype of rs776746 showed a significant association (RR = 1.613; p = 0.035) with allograft rejection. In addition, cox regression analysis showed that the presence of the "CA" genotype of rs4646453 increased (HR = 7.258; 95% CI = 1.354-38.904) the risk of development of pathological events, respectively. Four variants of CYP3A5 were synergistically associated with the TAC dose determination. In addition, rs776746 and rs4646453 may be associated with allograft rejection and pathological events, respectively.

Drug-gene interactions in older patients with coronary artery disease

BackgroundOlder patients with coronary artery disease (CAD) are particularly vulnerable to the efficacy and adverse drug reactions, and may therefore particularly benefit from personalized medication. Drug–gene interactions (DGIs) occur when an individual’s genotype affects the pharmacokinetics and/or pharmacodynamics of a victim drug.ObjectivesThis study aimed to investigate the impact of cardiovascular-related DGIs on the clinical efficacy and safety outcomes in older patients with CAD.MethodsHospitalized older patients (≥ 65 years old) with CAD were consecutively recruited from August 2018 to May 2022. Eligible patients were genotyped for the actionable pharmacogenetic variants of CYP2C9, CYP2C19, CYP2D6, CYP3A5, and SLCO1B1, which had clinical annotations or implementation guidelines for cardiovascular drugs. Allele frequencies and DGIs were determined in the cohort for the 5 actionable PGx genes and the prescribed cardiovascular drugs. All patients were followed up for at least 1 year. The influence of DGIs on the cardiovascular drug-related efficacy outcomes (all-cause mortality and/or major cardiovascular events, MACEs) and drug response phenotypes of “drug-stop” and “dose-decrease” were evaluated.ResultsA total of 1,017 eligible older patients with CAD were included, among whom 63.2% were male, with an average age of 80.8 years old, and 87.6% were administrated with polypharmacy (≥ 5 medications). After genotyping, we found that 96.0% of the older patients with CAD patients had at least one allele of the 5 pharmacogenes associated with a therapeutic change, indicating a need for a therapeutic change in a mean of 1.32 drugs of the 19 cardiovascular-related drugs. We also identified that 79.5% of the patients had at least one DGI (range 0–6). The median follow-up interval was 39 months. Independent of age, negative association could be found between the number of DGIs and all-cause mortality (adjusted HR: 0.84, 95% CI: 0.73–0.96, P = 0.008), and MACEs (adjusted HR: 0.84, 95% CI: 0.72–0.98, P = 0.023), but positive association could be found between the number of DGIs and drug response phenotypes (adjusted OR: 1.24, 95% CI: 1.05–1.45, P = 0.011) in the elderly patients with CAD.ConclusionsThe association between cardiovascular DGIs and the clinical outcomes emphasized the necessity for the integration of genetic and clinical data to enhance the optimization of cardiovascular polypharmacy in older patients with CAD. The causal relationship between DGIs and the clinical outcomes should be established in the large scale prospectively designed cohort study.

Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Studies Related to Vincristine-Induced Peripheral Neuropathy in Chinese Pediatric ALL Patients.

Vincristine (VCR) can cause vincristine-induced peripheral neuropathy (VIPN) during the treatment of acute lymphoblastic leukemia (ALL) and the mechanisms are complicated. The aim of this study was to investigate the influencing factors on the population pharmacokinetics (PopPK) and pharmacodynamics (PD) related to VIPN, including clearance routes, drug-drug interactions (DDI), and genetic characteristics. Pediatric patients being treated for ALL were recruited to PK study where VCR and its metabolite (M1) were measured using a novel assay. The incidence of VIPN was also recorded. DNA sequencing of relevant PK and PD genes was performed. PopPK and PK/PD models were developed, pharmacogenetic and DDI analyses were conducted. In total, 79 children were recruited. The results showed that allometric scaling, ABCB1-rs1128503 genotype, and posaconazole (POS) significantly improved the PopPK model fit. VIPN was significantly correlated with the exposure of VCR. Co-administration with POS shifted the effect curve for VIPN to the left, indicating increased VIPN risk at the same exposure levels. No significant effects on VIPN were observed for CYP3A5 (rs776746), CYP3A4 (rs2242480), CEP72 (rs924607), or various ABCB1 variants (rs1128503, rs2032582, rs1045642, rs4728709, rs4148737, and rs10276036), nor with the co-administration of fluconazole or dasatinib. In summary, co-administration of POS increased VCR exposure by 0.4-fold and raised the risk of VIPN, with an occurrence probability generally exceeding 0.7. Therapeutic drug monitoring of VCR in clinical practice may be necessary to enable appropriate dose adjustments and individualized treatment.

The effect of gene polymorphism on ticagrelor metabolism: an in vitro study of 22 CYP3A4 variants in Chinese Han population.

Ticagrelor is a novel oral antiplatelet agent which can selectively inhibit P2Y12 receptor. Bleeding and dyspnea are common adverse reactions of ticagrelor in clinic. The side effects of ticagrelor are correlated with the plasma concentration of ticagrelor. This study aimed to evaluate the catalytic characteristics of 22 CYP3A4 alleles identified in the Chinese Han population on the metabolism of ticagrelor in vitro, focusing on the effect of CYP3A4 polymorphism on ticagrelor metabolism. In this study, insect cells were used to express 22 CYP3A4 variants, which were then incubated with 1-50 µM ticagrelor at 37 °C for 30 minutes to obtain the metabolite (AR-C124910XX). AR-C124910XX was detected by UHPLC-MS/MS to calculate the kinetic parameters, including Km, Vmax and CLint. Compared to the wild-type, most CYP3A4 alleles exhibited significant differences in intrinsic clearance. The intrinsic clearance of CYP3A4*11, *18 and *33 was much higher than that of wild-type; four variants exhibited similar intrinsic clearance values as the wild-type enzyme; The remaining 14 variants showed significantly reduced intrinsic clearance values, ranging from 1.48% to 75.11% of the wild-type; CYP3A4*30 displayed weak or no activity. This study conducted a comprehensive assessment of the effect of CYP3A4 variants on ticagrelor's metabolism. The results suggested that there is allele-specific activity towards ticagrelor in vitro. These findings can provide some insights and predictions for treatment strategies and risk assessments associated with ticagrelor in clinical practice.

Association of genetic variants in CYP3A5, DRD2 and NK1R with opioid overdose

In 2023, 3651 Ohioans died because of an opioid overdose. Of those opioid overdoses, 3579 (98%) of which were attributed to fentanyl. We evaluated the association between 180 candidate single nucleotide polymorphisms (SNPs) and self-reported, nonfatal opioid overdose history from a prospective sample of 1301 adult patients (≥18 years of age) seen in three urban emergency departments in Ohio. Candidate SNPs included 120 related to the dopamine reward pathway and 60 related to pharmacokinetics. Of the 821 patients who reported having been exposed to opioids in their lifetime, 95 (11.6%) also reported having experienced an opioid-related overdose. Logistic regression, adjusting for age and biologic sex, was used to characterize the association between each SNP and opioid overdose, correcting for multiple comparisons. Three SNPs, located in three different genes were associated with opioid overdose: increased odds with CYP3A5 (rs776746) and DRD2 (rs4436578), and decreased odds with NKIR (rs6715729). Homozygotic CYP3A5 (rs776746) had the highest adjusted odds ratio (OR) of 6.96 (95% CI [2.45, 29.23]) and homozygotic NK1R (rs6715729) had the lowest OR of 0.28 (95% CI [0.14, 0.54). Given that CYP3A5 (rs776746) has been associated with increased plasma concentrations of fentanyl, rs776746 could potentially be utilized as a prognostic risk indicator for the potential of an opioid overdose. NK1R regulates the expression of the neurokinin-1 receptor, a regulator of respiration and NK1R (rs6715729) represents a novel genetic marker for a decreased risk of opioid overdose risk.

Pharmacogenetic insights into ABCB1, ABCC2, CYP1A2, and CYP2B6 variants with epilepsy susceptibility among Egyptian Children: A retrospective case-control study

BackgroundPediatric epilepsy is a complicated neuropsychiatric disorder that is characterized by recurrent seizures and unusual synchronized electrical activities within brain tissues. It has a substantial effect on the quality of life of children, thus understanding of the hereditary considerations influencing epilepsy susceptibility and the response to antiepileptic medications is crucial. This study focuses on assessing the correlation of the ABCB1, ABCC2, CYP1A2, and CYP2B6 genetic polymorphisms with the susceptibility to epileptic seizures and their contributions to antiepileptic medication throughout the course of the disease. MethodsThis study included 134 Egyptian epileptic children, comprising 67 drug-responsive and 67 drug-resistant patients, along with 124 healthy controls matching for age, gender, and geographical district. Genotyping of the rs2032582, rs717620, rs2273697, rs762551, and rs3745274 variants was performed using the PCR technique. Statistical analyses, including haplotype, multivariate, logistic regression, and bioinformatics approaches, were conducted to evaluate the associations within the disease. ResultsThe ABCC2*rs717620 (T allele) revealed an increased risk of epilepsy compared to healthy controls (OR = 2.12, p-value < 0.001), with the rs717620 (C/T + T/T genotypes) showing significant differences between drug-responsive and drug-resistant patients (p-value < 0.05). Moreover, the ABCC2*rs2273697 (A allele) indicated a decreased risk of epileptic seizures compared to healthy controls (OR = 0.51, p-value = 0.033), with the rs2273697 (G/A + A/A genotypes) indicating a significant association with drug-resistant patients (OR = 0.21, p-value = 0.002). The rs717620*T/rs2273697*G haplotype was significantly correlated with an elevated risk of epileptic seizures within drug-responsive patients (OR = 2.26, p-value = 0.019). Additionally, the CYP1A2*rs762551 (A allele) represented a protective effect against epilepsy susceptibility (OR = 0.50, p-value < 0.001), with the rs762551 (G/A + A/A genotypes) disclosing a substantial association with a decreased risk of epileptic seizures among drug-resistant patients compared to drug-responsive patients (OR = 0.07, p-value < 0.001). Conversely, the ABCB1*rs2032582 (G allele) and the CYP2B6*rs3745274 (T allele) did not attain a significant difference with the epilepsy risk compared to healthy controls (p-value > 0.05). ConclusionsThe findings of our study emphasize the importance of pharmacogenetic screening in epilepsy research, particularly regarding to drug-resistant patients. The ABCC2*rs717620 variant conferred a significant correlation with elevated risk of epileptic seizures, while the ABCC2*rs2273697 and CYP1A2*rs762551 variants confirmed their contributions as protective markers against epilepsy development. Conversely, the ABCB1*rs2032582 and CYP2B6*rs3745274 alleles were not considered as independent risk factors with the course of epilepsy disease.

Renin and CYP P450 gene variations significantly associated with essential hypertension: A prospective pharmacogenomics study

ObjectiveThis study aims to investigate the association between Renin-angiotensin aldosterone system (RAAS) and Cytochrome P450 gene polymorphisms in hypertension patients of the South Indian population using pharmacogenomics profile. MethodsHypertension cases (N = 147) and control subjects (n = 150) were collected from Tamil Nadu, India. A case-control association study was conducted to assess the involvement of RAAS gene polymorphisms (REN rs397514691, REN rs544315427, REN rs567667202) and CYP gene polymorphisms (CYP2D6 rs754164689, CYP2D6 rs1058172, CYP3A4 rs765598920) in essential hypertensive patients. Genotyping was performed using the PCR-RFLP method, and significant results were validated through RT-PCR analysis. ResultsThe genotype and allele distribution of REN rs397514691 and rs544315427 variants significantly associated with hypertensive patients (Variant Allele Frequency (VAF) = 0.11; VAF = 0.27, respectively). CYP2D6 polymorphisms rs754164689 and rs1058172 variant alleles were significantly associated with female hypertensive patients, suggesting a potential risk allele for essential hypertension in the South Indian population. REN and CYP3A4 variants, highly connected in pharmacology action, were validated through RT-PCR amplification studies, providing new insights into their role in the development of hypertension. Association confirmation was achieved through multifactor dimensionality reduction analysis. ConclusionThe genes associated with specific variants, particularly REN and CYP2D6, may serve as potential markers for the early diagnosis of hypertension and as new drug targets, particularly in the female population.

Fine-mapping the CYP2A6 regional association with nicotine metabolism among African American smokers.

The nicotine metabolite ratio (NMR; 3'hydroxycotinine/cotinine) is a stable biomarker for CYP2A6 enzyme activity and nicotine clearance, with demonstrated clinical utility in personalizing smoking cessation treatment. Common genetic variation in the CYP2A6 region is strongly associated with NMR in smokers. Here, we investigated this regional association in more detail. We evaluated the association of CYP2A6 single-nucleotide polymorphisms (SNPs) and * alleles with NMR among African American smokers (N = 953) from two clinical trials of smoking cessation. Stepwise conditional analysis and Bayesian fine-mapping were undertaken. Putative causal variants were incorporated into an existing African ancestry-specific genetic risk score (GRS) for NMR, and the performance of the updated GRS was evaluated in both African American (n = 953) and European ancestry smokers (n = 933) from these clinical trials. Five independent associations with NMR in the CYP2A6 region were identified using stepwise conditional analysis, including the deletion variant CYP2A6*4 (beta = -0.90, p = 1.55 × 10-11). Six putative causal variants were identified using Bayesian fine-mapping (posterior probability, PP = 0.67), with the top causal configuration including CYP2A6*4, rs116670633, CYP2A6*9, rs28399451, rs8192720, and rs10853742 (PP = 0.09). Incorporating these putative causal variants into an existing ancestry-specific GRS resulted in comparable prediction of NMR within African American smokers, and improved trans-ancestry portability of the GRS to European smokers. Our findings suggest that both * alleles and SNPs underlie the association of the CYP2A6 region with NMR among African American smokers, identify a shortlist of variants that may causally influence nicotine clearance, and suggest that portability of GRSs across populations can be improved through inclusion of putative causal variants.

Caffeine Consumption and Interaction with ADORA2A, CYP1A2 and NOS1 Variants Do Not Influence Age at Onset of Machado-Joseph Disease.

The age at onset (AO) of Machado-Joseph disease (SCA3/MJD), a disorder due to an expanded CAG repeat (CAGexp) in ATXN3, is quite variable and the role of environmental factors is still unknown. Caffeine was associated with protective effects against other neurodegenerative diseases, and against SCA3/MJD in transgenic mouse models. We aimed to evaluate whether caffeine consumption and its interaction with variants of caffeine signaling/metabolization genes impact the AO of this disease. a questionnaire on caffeine consumption was applied to adult patients and unrelated controls living in Rio Grande do Sul, Brazil. AO and CAGexp were previously determined. SNPs rs5751876 (ADORA2A), rs2298383 (ADORA2A), rs762551 (CYP1A2) and rs478597 (NOS1) were genotyped. AO of subgroups were compared, adjusting the CAGexp to 75 repeats (p < 0.05). 171/179 cases and 98/100 controls consumed caffeine. Cases with high and low caffeine consumption (more or less than 314.5mg of caffeine/day) had mean (SD) AO of 35.05 (11.44) and 35.43 (10.08) years (p = 0.40). The mean (SD) AO of the subgroups produced by the presence or absence of caffeine-enhancing alleles in ADORA2A (T allele at rs5751876 and rs2298383), CYP1A2 (C allele) and NOS1 (C allele) were all similar (p between 0.069 and 0.516). Caffeine consumption was not related to changes in the AO of SCA3/MJD, either alone or in interaction with protective genotypes at ADORA2A, CYP1A2 and NOS1.

Pattern of CYP3A5 and MDR-1 single nucleotide polymorphism and its impact on Tacrolimus levels and clinical outcomes in living renal allograft recipient

Abstract Introduction Renal transplant is best form of renal replacement therapy. Most favored immunosuppression includes Tacrolimus, mycophenolate mofetil and steroids. Tacrolimus has narrow therapeutic index and requires therapeutic drug monitoring (TDM). However, there is wide variation in tacrolimus level with weight based fixed dosage regimens. This variability is due to polymorphism of major pathways of metabolism ie CYP3A5 and MDR1 genes. Fast metabolizer require higher dosage and slow metabolizer require lower dosage. Genotype based dosing strategy may be useful to achieve early therapeutic level and reduce infections and rejections. Methodology 160 transplant patients at tertiary care hospital in India were included in this study from 2016 to 2018. Genetic polymorphism analysis in CYP3A5 and MDR1 gene was carried out at time of transplant. All patients were given a fixed weight-based dosage of Tacrolimus. Data was analyzed in relation to genotype polymorphism. Results and discussion 69.2% of Wild variants of CYP 3A5 (Fast metabolizers) have low initial tacrolimus levels. 51.5% of Homo variants (Slow metabolizers) have high initial tac levels. However, all variants achieve optimum tacrolimus levels at same time (mean 12.4 days). There were higher number of infections among slow metabolizers. Conclusion A fixed dosing regimen with TDM result in high and low initial tacrolimus levels in slow and fast metabolizers respectively and more infections in slow metabolizers. However, graft rejections being fewer in number, were not different. A larger sample with genotype based dosing is required to test such a strategy.

Pharmacokinetics (PK) and pharmacogenomics (PGx) of ribociclib (ribo) in Black patients with metastatic breast cancer (mBC): The LEANORA study.

1581 Background: Ribo is metabolized by CYP3A and used for the treatment of patients with hormone receptor-positive (HR+)/HER2- mBC. FDA recommends dose reduction if used with CYP3A inhibitors due to a 3.2x increase ribo area-under-the-curve (AUC). It is unknown if modifications are needed in patients who lack enzyme activity (e.g., genetic CYP3A5 poor metabolizers (PM)). CYP3A5varies by genetic ancestry, is known to affect dosing for other drugs (e.g., tacrolimus). CYP3A5, ~85% of people of European ancestry are PM, ~85% of African ancestry are normal or intermediate metabolizers (NM, IM), which may impact ribo exposure and response. 2 percent (41/2066) enrolled in MONALEESA 2, 3, and 7 were Black. Methods: This prospective, multicenter cohort study (NCT04657679) assessed the PK and PGx of ribo (600 mg daily + letrozole/fulvestrant) in self-identified Black women with HR+/HER2- mBC. PK (0.5, 1, 2, 4, and 6 hours after ribo) and PGx studies were performed during cycle 1 via liquid chromatography with tandem mass spectrometry and PharmacoScan (ThermoFisher) microarray, which tests 1,191 genes. Including variants in CYP3A5*3, *6,and *7. Phenotypes assigned: PM (2 variant alleles), intermediate metabolism (IM; 1 variant allele), NM (0 variant alleles). The area under the curve (AUCtau) was compared with the exact Wilcoxon rank-sum test; Fisher’s exact test assessed the AEs and grade 3+ AEs to day 28. Results: 14 completed the trial. CYP3A5 phenotypes were PM (7), IM (6), and NM (1). The primary endpoint, AUCtau, was similar between CYP3A5 PM (39,230 hr*ng/mL; interquartile range [IQR]: 18,745 to 57,566 hr*ng/mL) vs. IM/NM (43,546 hr*ng/mL; IQR: 35,298 to 46,647 hr*ng/mL; p = 0.38). Other PK properties were similar between groups (table). There was a non-statistically significant higher number of AEs and grade 3+ AEs in PMs, when compared to NM/IMs. Study was not powered to assess differences in AEs. Conclusions: This cohort study detected no association between CYP3A5 genotype and ribo exposure. However, PMs may have more AEs relative to IMs/NMs. Future steps include exploring the impact of rare variants, including ~70 variants in CYP3A 4 and 5, on ribo exposure in this population. We will explore the role of clinical and genetic factors on the interindividual variability of ribo. Diverse patient representation in clinical trials is critical to ensure research findings are applicable to all patients. Clinical trial information: NCT04657679 .[Table: see text]

The influence of drug-induced metabolic enzyme activity inhibition and CYP3A4 gene polymorphism on aumolertinib metabolism

The purpose of this study is to clarify the drug interaction profile of aumolertinib, and the influence of CYP3A4 genetic polymorphism on aumolertinib metabolic characteristics. Through microsomal enzyme reactions, we screened 153 drugs and identified 15 that significantly inhibited the metabolism of aumolertinib. Among them, telmisartan and carvedilol exhibited potent inhibitory activities in rat liver microsomes (RLM) and human liver microsomes (HLM). In vivo, the pharmacokinetic parameters of aumolertinib, including AUC and Cmax, were significantly altered when co-administered with carvedilol, with a notable decrease in the clearance rate CLz/F. Interestingly, the pharmacokinetic parameters of the metabolite HAS-719 exhibited a similar trend as aumolertinib when co-administered. Mechanistically, both telmisartan and carvedilol exhibited a mixed-type inhibition on the metabolism of aumolertinib. Additionally, we used a baculovirus-insect cell expression system to prepare 24 recombinant CYP3A4 microsomes and obtained enzymatic kinetic parameters using aumolertinib as a substrate. Enzyme kinetic studies obtained the kinetic parameters of various CYP3A4 variant-mediated metabolism of aumolertinib. Based on the relative clearance rates, CYP3A4.4, 5, 7, 8, 9, 12, 13, 14, 17, 18, 19, 23, 24, 33, and 34 showed significantly lower clearance rates compared to the wild-type. Among the different CYP3A4 variants, the inhibitory potency of telmisartan and carvedilol on the metabolism of aumolertinib also varied. The IC50 values of telmisartan and carvedilol in CYP3A4.1 were 6.68 ± 1.76 μM and 0.60 ± 0.25 μM, respectively, whereas in CYP3A4.12, the IC50 exceeded 100 μM. Finally, we utilized adeno-associated virus to achieve liver-specific high expression of CYP3A4*1 and CYP3A4*12. In the group with high expression of the less active CYP3A4*12, the magnitude of the drug-drug interaction was significantly attenuated. In conclusion, CYP3A4 genetic polymorphism not only influences the pharmacokinetic characteristics of aumolertinib, but also the inhibitory potency of telmisartan and carvedilol on it.

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.

Association of CYP3A4*1B, CYP3A4*22 and CYP3A5*3 polymorphisms carriage with efficacy and safety of tamsulosin in patients with benign prostatic hyperplasia

Tamsulosin is a first-line drug in the treatment of lower urinary tract symptoms (LUTS) in benign prostatic hyperplasia (BPH). Despite high estimates of its efficacy and safety, it rates may vary due to genetic polymorphisms of genes for the enzymes involved in the drugs metabolism.The aim of the work was to evaluate the carriage influence of genes polymorphisms of the CYP3A enzymes group of tamsulosin metabolizers on the efficacy and safety of therapy in patients with LUTS in BPH.Materials and methods. A total of 142 patients with LUTS, with an established BPH diagnosis (N40 according to ICD-10) were included in the study and underwent all stages. All patients received monotherapy with tamsulosin 0.4 mg/day for at least 8 weeks. An IPSS questionnaire with the definition of quality of life, a prostate ultrasound with the determination of the prostate volume and residual urine, as well as uroflowmetry, were used to evaluate the results of the treatment. Controls were performed at 2, 4 and 8 weeks from the start of the therapy. The carriage of polymorphic markers CYP3A4 (*1B, *22) and CYP3A5*3 was determined in patients; HPLC was used to determine drug concentrations in blood plasma and levels of cortisol and its metabolite 6-beta-hydroxycortisol in urine to assess the phenotypic activity of CYP3A.Results. No statistically significant associations between CYP3A phenotype (defined by CYP3A4 and CYP3A5 genotypes) and clinical parameters of the tamsulosin therapy efficacy and the safety assessment in the studied sample of patients were found (p &gt;0.05). Similar data were obtained for individual variants of CYP3A4*1B, CYP3A4*22, CYP3A5*3 (p &gt;0.05). The comparison of the tamsulosin residual equilibrium concentration values in patients in the study sample with respect to the carriers of CYP3A4 and CYP3A5 gene variants did not reveal the presence of significant differences in either CYP3A phenotypes and carriers and non-carriers of individual CYP3A4*1B (p=0.57), CYP3A4*22 (p=0.37) and CYP3A5*3 (p=0.76) variants. No association was found between the metabolic ratio of 6-beta-hydroxycortisol / cortisol in urine and the CYP3A phenotype encoded by a combination of genotypes of CYP3A4 and CYP3A5 gene variants (p &gt;0.05).Conclusion. A possible association between the carriage of CYP3A4*1B, CYP3A4*22, CYP3A5*3 variants, a CYP3A activity assessed by the content of an endogenous substrate of this isoenzyme and its metabolite in urine, the level of plasma concentration of the drug, and the efficacy and safety of tamsulosin, has not been confirmed. The contribution of CYP3A4 and CYP3A5 genetic polymorphisms to clinical parameters of the tamsulosin therapy requires a further study.

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

BackgroundDespite 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.MethodsPatients 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.ResultsA 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.ConclusionsThe study findings show that CYP2B6 and CYP3A5 pharmacogenetic variations may lead to higher plasma exposure of AL metabolites.

Influence of Genetic Polymorphisms in CYP3A5, CYP3A4, and MDR1 on Tacrolimus Metabolism after kidney transplantation

Kidney transplantation stands as the ultimate recourse for restoring vital organ functions, particularly in cases of end-stage kidney disease where alternative treatments, such as dialysis, prove less effective. With over 102,000 kidney transplants conducted globally in 2022, the demand for organ transplantation is ever-increasing, fueled by a rising incidence of end-stage renal disease attributed to causes like diabetes and hypertension.&lt;br /&gt; Despite significant advancements in kidney transplantation, immunosuppressive therapy remains crucial to preventing graft rejection. Tacrolimus (TAC), a calcineurin inhibitor, plays a pivotal role in this regard. Discovered in 1984, TAC inhibits T-lymphocyte activation, preventing acute rejection by disrupting the transcription of crucial genes involved in early T-cell activation. However, the use of TAC is not without challenges. The drug exhibits serious side effects, a narrow therapeutic index, and unpredictable pharmacokinetics. Therapeutic drug monitoring (TDM) becomes imperative in daily practice to maintain TAC blood concentrations within the therapeutic range. This literature review delves into the genetic aspects influencing TAC metabolism, focusing on key polymorphisms in CYP3A5, CYP3A4, and ABCB1 genes. Genetic variations in CYP3A5, a major enzyme in TAC metabolism, impact enzyme activity, necessitating personalized dosing strategies. CYP3A4 polymorphisms, especially CYP3A4*22, demonstrate associations with altered TAC clearance and dose requirements. The ABCB1 gene, encoding P-glycoprotein, another player in TAC pharmacokinetics, also exhibits polymorphisms influencing drug absorption and distribution. The ABCB1 3435C&amp;gt;T variant, in particular, shows potential implications on Tacrolimus bioavailability. Understanding these genetic variations aids in the development of personalized dosing regimens. Studies suggest that tailoring TAC doses based on CYP3A5 genotypes significantly improves the proportion of patients achieving therapeutic concentrations. Additionally, incorporating genetic information, particularly CYP3A4*22, into dosing strategies enhances the precision of TAC therapy, reducing the risk of adverse effects.

CYP2C8 rs11572080 and CYP3A4 rs2740574 risk genotypes in paclitaxel-treated premenopausal breast cancer patients

Breast cancer (BC) is the most prevalent malignancy in women globally. At time of diagnosis, premenopausal BC is considered more aggressive and harder to treat than postmenopausal cases. Cytochrome P450 (CYP) enzymes are responsible for phase I of estrogen metabolism and thus, they are prominently involved in the pathogenesis of BC. Moreover, CYP subfamily 2C and 3A play a pivotal role in the metabolism of taxane anticancer agents. To understand genetic risk factors that may have a role in pre-menopausal BC we studied the genotypic variants of CYP2C8, rs11572080 and CYP3A4, rs2740574 in female BC patients on taxane-based therapy and their association with menopausal status. Our study comprised 105 female patients with histologically proven BC on paclitaxel-therapy. They were stratified into pre-menopausal (n = 52, 49.5%) and post-menopausal (n = 53, 50.5%) groups. Genotyping was done using TaqMan assays and employed on Quantstudio 12 K flex real-time platform. Significant increased frequencies of rs11572080 heterozygous CT genotype and variant T allele were established in pre-menopausal group compared to post-menopausal group (p = 0.023, 0.01, respectively). Moreover, logistic regression analysis revealed a significant association between rs11572080 CT genotype and premenopausal BC. However, regarding rs2740574, no significant differences in genotypes and allele frequencies between both groups were detected. We reported a significant association between CYP2C8 genotypic variants and premenopausal BC risk in Egyptian females. Further studies on larger sample sizes are still needed to evaluate its importance in early prediction of BC in young women and its effect on treatment outcome.

Abstract 4369: CYP3A5 promotes aggressive and therapeutically resistant prostate cancer by modulating AR and Wnt signaling: Implications for racially disparate clinical outcomes

Abstract Prostate cancer (PC) is the second leading cause of cancer-related death in American men, which disproportionately affects Black/African American (AA) men. The androgen receptor (AR) signaling plays a pivotal role in PC development and is a primary target for intervention in patients with advanced disease. Aberrant activation of AR is also suggested to play a significant role in castration-resistant prostate cancer (CRPC). Despite advancements in anti-androgen therapies with new targeting agents, such as enzalutamide, metastatic CRPC (mCRPC) remains incurable. CYP3A5, a monooxygenase expressed in the prostate, liver and intestine, is involved in drug metabolism and steroid biosynthesis. We earlier reported that intratumoral CYP3A5 activated AR signaling by facilitating its nuclear translocation of AR. More notably, we found a higher CYP3A5 expression in AAs, attributed to the *1 CYP3A5 variant, as compared to non-Hispanic White Americans (NHWA) possessing the *3 variant. Analysis of RNA-seq data using patient tumor samples revealed that elevated CYP3A5 in AA PC patients was associated with Wnt-β catenin signaling activation via TCF4 overexpression. Here, we investigated the role of CYP3A5 in enzalutamide resistance and Wnt signaling by generating enzalutamide-resistant PC cell lines of NHWA (low CYP3A5-LNCaP) and AA-origin (high CYP3A5-MDAPCa2b). RT-qPCR assay was used to examine the changes in AR and CYP3A5 expression between the parental and the enzalutamide-resistant cell lines. The data show heightened CYP3A5 expression in enzalutamide-resistant cells of AA origin (MDAPCa2b/EnzR) but not of NHWA origin (LNCaP/EnzR). Interestingly, MDAPCa2b/EnzR exhibited no change in AR levels whereas it was increased in LNCaP/EnzR cells relative to parental lines. A loss of function assay was performed for siRNA-mediated silencing of CYP3A5 to study its effect on Wnt signaling. RNA sequencing results show that CYP3A5 inhibition in MDAPCa2b downregulated Wnt pathway genes (Wnt5A, Wnt10B, Wnt11, Fzd2, and Dvl3). These observations align with our previous RNA seq results using patient samples where we observed upregulated Wnt-β catenin signaling in high CYP3A5 expressing patient tumor samples. Western analysis post-CYP3A5 inhibition in LNCaP and MDAPCa2b cells revealed upregulated Axin and downregulated LRP6 and Dvl-3, signifying CYP3A5's regulation of the canonical Wnt-β catenin pathway. Additionally, MDAPCa2b saw downregulated Wnt 5A and Wnt 10B, known to influence the Wnt non-canonical pathway. Altogether, our data suggest that *1 CYP3A5 variant in AAs likely contributes to aggressive behavior and therapeutic resistance of PC and serves as a molecular determinant of disparate clinical outcomes. Citation Format: Jake McLean, Ajay P. Singh, Edwin Oh, Ranjana Mitra. CYP3A5 promotes aggressive and therapeutically resistant prostate cancer by modulating AR and Wnt signaling: Implications for racially disparate clinical outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4369.

Genome-Wide Association Study of Atorvastatin Pharmacokinetics: Associations With SLCO1B1, UGT1A3, and LPP.

In a genome-wide association study of atorvastatin pharmacokinetics in 158 healthy volunteers, the SLCO1B1 c.521T>C (rs4149056) variant associated with increased area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) of atorvastatin (P = 1.2 × 10-10), 2-hydroxy atorvastatin (P = 4.0 × 10-8), and 4-hydroxy atorvastatin (P = 2.9 × 10-8). An intronic LPP variant, rs1975991, associated with reduced atorvastatin lactone AUC0-∞ (P = 3.8 × 10-8). Three UGT1A variants linked with UGT1A3*2 associated with increased 2-hydroxy atorvastatin lactone AUC0-∞ (P = 3.9 × 10-8). Furthermore, a candidate gene analysis including 243 participants suggested that increased function SLCO1B1 variants and decreased activity CYP3A4 variants affect atorvastatin pharmacokinetics. Compared with individuals with normal function SLCO1B1 genotype, atorvastatin AUC0-∞ was 145% (90% confidence interval: 98-203%; P = 5.6 × 10-11) larger in individuals with poor function, 24% (9-41%; P = 0.0053) larger in those with decreased function, and 41% (16-59%; P = 0.016) smaller in those with highly increased function SLCO1B1 genotype. Individuals with intermediate metabolizer CYP3A4 genotype (CYP3A4*2 or CYP3A4*22 heterozygotes) had 33% (14-55%; P = 0.022) larger atorvastatin AUC0-∞ than those with normal metabolizer genotype. UGT1A3*2 heterozygotes had 16% (5-25%; P = 0.017) smaller and LPP rs1975991 homozygotes had 34% (22-44%; P = 4.8 × 10-5) smaller atorvastatin AUC0-∞ than noncarriers. These data demonstrate that genetic variation in SLCO1B1, UGT1A3, LPP, and CYP3A4 affects atorvastatin pharmacokinetics. This is the first study to suggest that LPP rs1975991 may reduce atorvastatin exposure. [Correction added on 6 April, after first online publication: An incomplete sentence ("= 0.017) smaller in heterozygotes for UGT1A3*2 and 34% (22%, 44%; P × 10-5) smaller in homozygotes for LPP noncarriers.") has been corrected in this version.].

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.