Background: Tuberculosis (TB) is an infectious disease transmitted through airborne, causing it highly contagious. Toll-like receptor 4 (TLR4) plays a crucial role in the pathogen destruction, including Mycobacterium tuberculosis.

Aims: This study aims to determine genotyping frequency of the TLR4 gene rs7873784 polymorphism and its impact on TB susceptibility in the healthy Thai population.

Methods: A total of 43 Thai TB patients and 54 healthy Thai control subjects were included in this study. After obtaining informed consent, 3 ml of whole blood was collected in EDTA tubes. Genomic DNA was then extracted by PureLink™ Genomic DNA Mini Kit and analyzed using QuantStudio™ 3 Real-Time PCR system. The association between TLR4 gene rs7873784 polymorphism and TB susceptibility was assessed by logistic regression analysis.

Results: The allele frequencies in TB group were approximately 85% for G and 15% for C, while in control group, they were approximately 91% for G and 9% for C. The CC genotype was associated with an approximately threefold increased risk of TB susceptibility compared to the GG genotype (wild-type carriers), although this finding was not statistically significant (p = 0.407).

Conclusions: The genetic variation of TLR4 rs7873784 may influence TB susceptibility in Thai population. Although the association was not statistically significant, the findings suggest a clinically potential link to increased TB risk in the Thai population. Future studies with larger sample sizes are warranted to confirm these finding and provide more definite conclusions.

Key words: Tuberculosis, Toll-like receptor 4, gene polymorphism, Thai population, SNPs rs7873784

Introduction: Allopurinol and its active metabolite oxypurinol is the primary treatment for gout. ATP-binding cassette subfamily G member 2 (ABCG2) functions as an efflux transporter for uric acid excretion, while human aldehyde oxidase 1 (hAOX1) is a uric acid-metabolizing enzyme sharing homology with xanthine oxidase. Genetic polymorphisms in ABCG2 rs2231142 and hAOX1 rs3731722 have been linked to variability in allopurinol response.

Aims: To investigate the relationship between ABCG2 rs2231142 and hAOX1 rs3731722 polymorphisms and plasma oxypurinol concentration to explain variability in allopurinol treatment response

Method: This cross-sectional study examined 37 gout patients from Hospital Canselor Tuanku Mukhriz. Plasma oxypurinol levels were analyzed using high-performance liquid chromatography with ultraviolet detection, while genotyping was performed through PCR-Sanger sequencing.

Results: All participants (86.5% male, mean age 58.0±14.2 years) carried the homozygous TT variant of ABCG2 rs2231142, while for hAOX1 rs3731722, 81.1% had the wild-type allele and 18.9% carried the heterozygous AG variant. No significant association was observed between hAOX1 rs3731722 and oxypurinol concentration in both unadjusted and adjusted models. However, allopurinol dose and creatinine clearance significantly influenced oxypurinol concentration (p=0.001, p=0.013). Notably, hAOX1 rs3731722 showed significant association with daily allopurinol dose (p<0.001).

Conclusion: While hAOX1 rs3731722 had no direct impact on oxypurinol concentration, its significant association with allopurinol dosing suggests potential influence on treatment requirements. The homogeneity of ABCG2 rs2231142 in our population prevented assessment of its impact on oxypurinol levels limiting our ability to evaluate its role in allopurinol therapy effectiveness

Keywords: ABCG2, hAOX1, allopurinol, oxypurinol, genetic polymorphism

Background: Mycophenolate mofetil (MMF) is widely used with other immunosuppressants to prevent organ rejection. It is hydrolyzed to its active form, mycophenolic acid (MPA), which is further metabolized into inactive mycophenolic acid glucuronide (MPAG) and active acyl-glucuronide (AcMPAG). MPA is extensively bound to albumin, and only free MPA is pharmacologically active. MPAG reflects UDP-glucuronosyltransferase activity, and AcMPAG is associated with gastrointestinal toxicity. Simultaneous quantification of free MPA and its metabolites provides comprehensive insight into MPA metabolism, potentially enhancing dose individualization to optimize immunosuppression while minimizing toxicity.

Aims: To develop and validate a multiplex liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the simultaneous quantification of free MPA, along with MPA metabolites, in plasma and saliva.

Methods: Absolute quantification of MPA, MPAG, and AcMPAG in plasma was achieved using LC-MS/MS. Analytical validation included assessments of sensitivity, linearity, precision, recovery, matrix effects, and carryover, following clinical laboratory guidelines.

Results: The developed assay enables the simultaneous quantification of MPA, MPAG, and AcMPAG with imprecision of 3.4%, 2.2%, and 1.8% for low, mid, and high MPA QCs; 5.9%, 1.8%, and 1.7% for MPAG QCs; and 9.1%, 2.2%, and 1.8% for AcMPAG QCs. LLOQs were 0.01 mg/L for MPA and MPAG and 0.05 mg/L for AcMPAG, with linear ranges of 50 mg/L (MPA), 150 mg/L (MPAG), and 4 mg/L (AcMPAG).

Conclusions: This validated assay enables accurate monitoring of MPA and its metabolites. Further studies will assess saliva as a non-invasive alternative for TDM in transplant patients.

Keywords: Immunosuppressant, mycophenolic acid, metabolites, LC-MS/MS, therapeutic drug monitoring, saliva

Background: Tacrolimus is cornerstone in immunosuppressive regimens for heart transplantation, with narrow therapeutic index and large inter- and intra- variabilities. Therapeutic drug monitoring is important for tacrolimus personalized dosing, but have some limitation for clinical application.
Aims: We aimed to establish and validate a population pharmacokinetic (PPK) model of tacrolimus, develop the model into a clinical decision support system (CDSS) for convenient use, and further compare the outcome of MIPD and traditional dosage.
Methods: Tacrolimus data were retrospectively collected from the records of 100 patients who received first heart transplantation. Tacrolimus PPK model was established by NONMEM. Information technology and Bayesian method are used to establish CDSS. The C0 and obtained rate for desired C0 of tacrolimus were compared between MIPD and empiric dosing.
Results: A one-compartment model with first order absorption and elimination was used to describe the disposition of tacrolimus in whole blood. Tacrolimus apparent clearance was significantly reduced in CYP3A5 nonexpressers (CYP3A5*3/*3), concomitant with azole antifungal drugs and Wuzhi capsule (WZ). Recommended dose regimens were obtained by simulations based on the established model. Based on MIPD, the percentage of achieved the therapeutic target is higher, the time to reach the target concentration is faster, and fewer dose adjustments are required.
Conclusions: MIPD for tacrolimus in heart transplantation is superior to the clinic-based dosage to achieve the therapeutic target.
Keywords: Model-Informed Precision Dosing, Tacrolimus, Heart transplantation

Background: Tacrolimus, an immunosuppressive agent, is widely used to treat various types of transplants, and controlling its blood concentration and therapeutic efficacy has always been a particularly critical issue of concern.

Aims: This retrospective analysis evaluated tacrolimus therapeutic drug monitoring (TDM) data to determine the optimal therapeutic window and guide treatment adjustments for transplant patients in real-world settings.

Methods: TDM data from outpatient and inpatient transplant patients (liver, kidney, cardiac, and hematopoietic stem cell transplants) at the First Affiliated Hospital of University of Science and Technology of China (Jan. 1, 2024–Dec. 31, 2024) were analyzed. Tacrolimus steady-state blood concentrations were monitored in 12,539 patients (10,718 outpatients and 1,821 inpatients).

Results: The interquartile range (P25–P75) of tacrolimus blood concentrations was 4.60–7.31 ng/mL. The outpatient concentrations ranged from 4.60–7.10 ng/mL (66.64% compliance), whereas the inpatient concentrations ranged from 4.77–9.25 ng/mL (70.35% compliance). Patients with multiple TDM sessions had significantly higher compliance rates than those with single sessions (P < 0.01). The interquartile ranges (compliance rates) of blood concentrations varied by transplant type: kidney (4.70–7.07 ng/mL, 68.71%), liver (3.97–8.11 ng/mL, 61.30%), hematopoietic stem cell (3.60–9.20 ng/mL, 60.84%), cardiac (5.55–8.98 ng/mL, 81.71%), and lung (4.80–10.19 ng/mL, 69.76%), and the differences were significant (P < 0.05).

Conclusions: The optimal tacrolimus therapeutic window may need re-evaluation for different transplant types to improve compliance and guide precision therapy.

Key Words: Transplant; Tacrolimus; Therapeutic drug monitoring; Therapeutic window; Individualized therapy

Background: CYP3A4 is an important drug-metabolizing enzyme, and its genetic variants may affect drug metabolism and drug-drug interactions. Imatinib is a commonly used anti-cancer drug, and CYP3A4 polymorphisms may influence its metabolism.

Aims: To investigate the catalytic activity of 26 CYP3A4 variants on imatinib metabolism and their drug interactions.

Methods: Ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was used to measure the concentration of imatinib's metabolite N-desmethyl imatinib. The study was conducted using an appropriate incubation system under constant temperature water to evaluate the impacts of CYP3A4 genetic polymorphisms and drug interactions on imatinib metabolism.

Results: Compared to CYP3A4.1, the intrinsic clearance (CLint) values of the 26 variants varied significantly, ranging from 2.34% to 120.57%. CYP3A4.14 showed an increase in CLint compared to CYP3A4.1, while the remaining 24 variants exhibited decreased catalytic activity for imatinib metabolism. Additionally, the metabolism of imatinib was inhibited to varying degrees by ketoconazole, itraconazole, and fluconazole in both CYP3A4.1 and CYP3A4.18. Most CYP3A4 variants showed similar enzyme activity patterns with different substrates, imatinib and cabozantinib, except for six variants (CYP3A4.3, .4, .10, .15, .29, and .31).

Conclusions: This study is the first to investigate the effects of 26 CYP3A4 variants on imatinib metabolism. The findings will contribute to the clinical evaluation of imatinib and assist in the personalization of therapy in clinical practice.

Key Words: Imatinib, CYP3A4 variants, metabolism , cabozantinib, microsomes

Background: Cytomegalovirus (CMV) disease is a life-threatening complication after lung transplantation. Valganciclovir (VGCV) is safe and highly effective in prophylaxis of CMV infection. However, early cessation by VGCV-induced myelosuppression leads to serious CMV disease. Recently, Nudix hydrolase (NUDT) 15 was identified as a key metabolic enzyme in the active metabolite of VGCV. Although genetic polymorphisms in NUDT15 are prevalent in East Asians, the impact of these polymorphisms on VGCV-induced myelosuppression remains to be unclear.

Aims: This study aims to assess the effect of NUDT15 single nucleotide polymorphisms on the incidence of neutropenia and valganciclovir cessation in lung transplant recipients.

Methods: We recruited 28 lung transplant patients with VGCV prophylaxis therapy. Genotyping in exon1–3 of NUDT15 was performed by Sanger sequencing. The cumulative incidence of neutropenia (neutrophil count < 1,500 /mm³) and neutropenia-related cessation within the one-year follow-up period were assessed in the wild-type group and the reduced-function group, which consisted of patients with NUDT15 single nucleotide polymorphisms.

Results: Of 28 patients, 9 (32.1%) were identified as carrying NUDT15 reduced-function polymorphisms. The nadir of the neutrophil count within the one-month observation period following treatment initiation was significantly lower in the reduced-function group (median, WT 4.01/mm³; reduced-function group 2.60/mm³). In the analysis of covariance using GCV trough levels as a covariate, the NUDT15 polymorphism was found to have a significant effect on the nadir of the neutrophil count (p<0.05).

Conclusions: NUDT15 polymorphisms increase the risk of neutropenia due to VGCV prophylaxis in lung transplant recipients.

Keywords: NUDT15, valganciclovir, lung transplantation

Background:Lung cancer is the leading cause of cancer-related deaths in China, with 19% of deaths, totaling 3.62 million cases. Non-small cell lung cancer (NSCLC) accounts for 85% of cases. ABCB1 gene polymorphism (rs1045642) may influence chemotherapy efficacy in NSCLC, particularly with platinum-based treatments, yet studies are limited, especially in Chinese populations.

Objective:To explore the correlation between the ABCB1 rs1045642 genotype and the progression-free survival of patients with advanced non-small cell lung cancer (NSCLC) receiving platinum-containing treatment regimens. 

Methods: Clinical data such as age, gender, tumor metastasis, etc. of newly - diagnosed patients with stage IIIB - IV lung cancer admitted to the First Affiliated Hospital of the University of Science and Technology of China (Anhui Provincial Hospital) between August 2020 and April 2022 were collected and the patients were followed up. The genotyping of ABCB1 rs1045642 polymorphism was performed using a fluorescence-based detection method. Kaplan-Meier survival analysis and COX proportional-hazards regression model were employed to analyze the influencing factors of prognosis. 

Results:Patients with the CC genotype of ABCB1 rs1045642 (n=34) exhibited a significantly better median progression-free survival (PFS) compared to those with the CT/TT genotype (n=49) (P=0.032). The ABCB1 rs1045642 genotype was identified as an independent factor affecting PFS in lung cancer patients treated with platinum-based regimens (P=0.018).
Conclusion:The ABCB1 rs1045642 genotype can be used to predict the efficacy of platinum-containing treatment regimens in patients with stage IIIB-IV lung cancer, providing a reference for the personalized administration of platinum-based drugs.

Key words:Non-small cell lung cancer; ABCB1 rs1045642; Platinum resistance

Background: Tuberculosis remains a high-burden disease in Thailand, with immunocompromised individuals, particularly those with diabetes mellitus, being at increased risk. Previous studies have suggested that the TLR4 variants rs11536889 and rs7873784 may be associated with TB susceptibility in diabetic patients. However, the available research is limited and inconclusive.

Aims: To determine the association between the genotype frequencies of rs11536889 and rs7873784 in the TLR4 gene and the risk of developing TB in Thai diabetic patients.

Methods: Diabetic patients were divided into two groups: Group 1 (without TB), and Group 2 (with TB). Blood samples were collected and processed using PureLink™ Genomic DNA Mini Kit for DNA extraction. Genotyping was performed by RT-PCR, and the associations were analyzed using logistic regression.

Results: Although statistical significance was not observed, carriers of CC genotype for rs11536889 had a 1.6-fold higher risk compared to wild-type carriers (p=0.633). For rs7873784, the CC genotype was absent in the TB group, so the association could not be analyzed. Meanwhile, the CG genotype was associated with decreased risk, but this finding was not statistically significant in either SNP.

Conclusions: Although the results were not statistically significant, they suggest a potential protective effect of the CC genotype for rs11536889. Further studies with larger sample sizes are needed to establish a reliable association and support the development of genetic screening measures for early intervention in diabetic patients in Thailand.

Key Words: TLR4, Diabetes mellitus, Tuberculosis, SNPs, Thai population

Objective: This study aimed to evaluate the safety and efficacy of antiplatelet therapy based on CYP2C19 genotype selection of different P2Y12 receptor antagonists in patients with intracranial aneurysms (IA) after stent-assisted coil embolization (SAC).
Methods: The study retrospectively analyzed the data of 332 IA patients who underwent SAC at the Second Affiliated Hospital of Zhejiang University School of Medicine in 2022, with an average age of 58.9 years.
Results: Patients were divided into five groups based on CYP2C19 genotype and received different antiplatelet treatment regimens. The results showed that 25 patients experienced intracranial ischemic events and 8 experienced hemorrhagic events. The incidence of hemorrhagic events in the intermediate metabolizer group treated with clopidogrel was significantly higher than that in the normal/fast metabolizer group; while in the slow metabolizer group, the risk of ischemic events in the clopidogrel group was higher than that in the ticagrelor group.
Conclusion: Antiplatelet treatment regimens guided by CYP2C19 gene testing can optimize efficacy and safety. Selecting regimens based on different metabolic types of patients helps balance the risk of ischemia and hemorrhage.