Role of the nuclear pregnane X receptor in drug metabolism and the clinical response

The pregnane X receptor (PXR) is an orphan nuclear receptor that regulates the expression of phase I and phase II drug metabolizing enzymes and transporters involved in the absorption, distribution, metabolism, and elimination of xenobiotics. PXR is expressed predominantly in the liver and intestine and resembles cytochrome P450s (CYPs), which is a phase I drug metabolizing enzyme. It is estimated that CYP 3As and CYP2Cs metabolize > 50% of all prescription drugs. PXR upregulates gene expression of these CYPs. Therefore, PXR plays a crucial role detoxifying xenobiotics and could potentially have effects on drug-drug interactions. PXR is reportedly responsible for activating a variety of target genes through cross-talk with other nuclear receptors and coactivators at transcriptional and translation levels. Recent findings have demonstrated the regulatory role of PXR and show the potential use of a PXR antagonist during drug therapy. In addition, genetic variations in the PXR gene are associated with the pharmacological effects of several drugs, and inter-individual differences in the clinical response are likely to be understood through these PXR polymorphisms. Many approaches have been used to explain the PXR regulatory mechanisms, such as microRNA-mediated PXR post-translational regulation and diverse PXR haplotype analysis. Understanding these PXR polymorphisms may lead to improving personalized therapeutic treatments

Comparison of pharmacogenomic information for drug approvals provided by the national regulatory agencies in Korea, Europe, Japan, and the United States

Pharmacogenomics, which is defined as the study of changes in the properties of DNA and RNA associated with drug response, enables the prediction of the efficacy and adverse effects of drugs based on patients’ specific genetic mutations. For the safe and effective use of drugs, it is important that pharmacogenomic information is easily accessible to clinical experts and patients. Therefore, we examined the pharmacogenomic information provided on drug labels in Korea, Europe, Japan, and the United States (US). The selection of drugs that include pharmacogenomic information was based on the drug list that includes genetic information from the Korea Ministry of Food and Drug Safety (MFDS) and US Food and Drug Administration (FDA) websites. Drug labels were retrieved from the sites of MFDS, FDA, European Medicines Agency, and Japanese Pharmaceuticals and Medical Devices Agency. Drugs were classified as per the Anatomical Therapeutic Chemical code, and the biomarkers, labeling sections, and necessity of genetic tests were determined. In total, 348 drugs were selected from 380 drugs with available pharmacogenomic information in Korea and the US after applying the inclusion and exclusion criteria. Of these drugs, 137, 324, 169, and 126 were with pharmacogenomics information in Korea, the US, Europe, and Japan, respectively. The most commonly represented drug class was antineoplastic and immunomodulating agents. Regarding the classification as per the mentioned biomarkers, the cytochrome P450 enzyme was the most frequently mentioned information, and the targeted anticancer drugs most commonly required genetic biomarker testing. The reasons for differences in drug labeling information based on country include differences in mutant alleles according to ethnicity, frequencies at which drug lists are updated, and pharmacogenomics-related guidelines. Clinical experts must continuously strive to identify and report mutations that can explain drug efficacy or side effects for safe drug use

Association of pre-operative medication use with post-operative delirium in surgical oncology patients receiving comprehensive geriatric assessment

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Abstract Background Older patients undergoing surgery tend to have a higher frequency of delirium. Delirium is strongly associated with poor surgical outcomes. This study evaluated the association between pre-operative medication use and post-operative delirium (POD) in surgical oncology patients receiving comprehensive geriatric assessment (CGA). Methods A total of 475 patients who were scheduled for cancer surgery and received CGA from January 2014 to June 2015 were included. Pre-operative medication review through CGA was conducted on polypharmacy (≥5 medications), delirium-inducing medications (DIMs), fall-inducing medications (FIMs), and potentially inappropriate medications (PIMs). POD was confirmed by psychiatric consultation, and DSM-V criteria were used for diagnosing delirium. The model fit of the prediction model was assessed by computing the Hosmer-Lemeshow goodness-of-fit test. Effect size was measured using the Nagelkerke R2. Discrimination of the model was assessed by an analysis of the area under receiver operating curve (AUROC). Results Two models were constructed for multivariate analysis based on univariate analysis; model I included dementia and DIM in addition to age and sex, and model II included PIM instead of DIM of model I. Every one year increase of age increased the risk of POD by about 1.1-fold. DIM was a significant factor for POD after adjusting for confounders (AOR 12.78, 95 % CI 2.83-57.74). PIM was also a significant factor for POD (AOR 5.53, 95 % CI 2.03-15.05). The Hosmer-Lemeshow test results revealed good fits for both models (χ2 = 3.842, p = 0.871 for model I and χ2 = 8.130, p = 0.421 for model II). The Nagelkerke R2 effect size and AUROC for model I was 0.215 and 0.833, respectively. Model II had the Nagelkerke R2effect size of 0.174 and AUROC of 0.819. Conclusions These results suggest that pharmacists comprehensive review for pre-operative medication use is critical for the post-operative outcomes like delirium in older patients

Role of the nuclear pregnane X receptor in drug metabolism and the clinical response

The pregnane X receptor (PXR) is an orphan nuclear receptor that regulates the expression of phase I and phase II drug metabolizing enzymes and transporters involved in the absorption, distribution, metabolism, and elimination of xenobiotics. PXR is expressed predominantly in the liver and intestine and resembles cytochrome P450s (CYPs), which is a phase I drug metabolizing enzyme. It is estimated that CYP 3As and CYP2Cs metabolize > 50% of all prescription drugs. PXR upregulates gene expression of these CYPs. Therefore, PXR plays a crucial role detoxifying xenobiotics and could potentially have effects on drug-drug interactions. PXR is reportedly responsible for activating a variety of target genes through cross-talk with other nuclear receptors and coactivators at transcriptional and translation levels. Recent findings have demonstrated the regulatory role of PXR and show the potential use of a PXR antagonist during drug therapy. In addition, genetic variations in the PXR gene are associated with the pharmacological effects of several drugs, and inter-individual differences in the clinical response are likely to be understood through these PXR polymorphisms. Many approaches have been used to explain the PXR regulatory mechanisms, such as microRNA-mediated PXR post-translational regulation and diverse PXR haplotype analysis. Understanding these PXR polymorphisms may lead to improving personalized therapeutic treatments

Association between Statin Use and Sensorineural Hearing Loss in Type 2 Diabetic Patients: A Hospital-Based Study

Statins have emerged as protective agents against sensorineural hearing loss (SNHL) associated with dyslipidemia, but the effects of statins on SNHL are not consistent. The purpose of this study was to investigate the association between statin use and the risk of SNHL using a hospital cohort. This nested case-control study included type 2 diabetic patients over the age of 18 years without a history of hearing loss. Of these, 1379 patients newly diagnosed with SNHL or tinnitus were classified as cases, and 5512 patients matched to the cases based on age, sex, and index year were classified as controls. Chi-squared tests were used to compare categorical variables between the two groups. Odds ratios (ORs) and adjusted odds ratios (AOR) were calculated from univariate and multivariable unconditional logistic regression analyses, respectively. There was a significant difference in the prevalence of statin use between the cases and controls (53.7% vs. 61.2%, respectively; p < 0.001). The use of statins in type 2 diabetic patients significantly reduced the risk of SNHL or tinnitus by 24.8% (95% CI 14.2–34.1%, p < 0.001) after controlling for confounders. Similar results were found for the association between statin use and SNHL (AOR = 0.706; 95% CI 0.616–0.811, p < 0.001). The protective effects of statins against SNHL were consistent regardless of age and sex. The use of statins for type 2 diabetic patients was significantly associated with a reduced risk of SNHL, regardless of age and sex. Further studies are needed, especially large cohort studies, to evaluate the long-term protective effects of statins

Effects of Ephedrine-Containing Products on Weight Loss and Lipid Profiles: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Ephedrine, the main active ingredient of mahuang, may lead to weight loss; however, it can also induce cardiovascular side effects. As ephedrine use remains controversial, this study aimed to systematically review previous studies on ephedrine-containing products and perform meta-analysis of the existing evidence on weight, blood pressure (BP), heart rate, and lipid change effects of ephedrine-containing products. We searched for placebo-controlled randomized studies in PubMed, Web of Science, and EMBASE until July 2021 using the following search terms: (ephedr* OR mahuang) AND (“weight loss” OR obes* OR overweight). Mean differences (MDs) and 95% confidence intervals (CIs) were calculated to evaluate the effects of ephedrine-containing products on weight, BP, heart rate, and lipid profiles. A total of 10 articles were included. Compared with the placebo group, the ephedrine-containing product group was associated with greater weight loss, with an MD of −1.97 kg (95% CI: −2.38, −1.57). In the ephedrine-containing product group, the mean heart rate was 5.76 beats/min higher than in the placebo group (95% CI: 3.42, 8.10), whereas intergroup differences in systolic and diastolic BP were not statistically significant. The ephedrine-containing product group had a significantly higher mean high-density lipoprotein cholesterol level (MD: 2.74 mg/dL; 95% CI: 0.94, 4.55), lower mean low-density lipoprotein cholesterol level (MD: −5.98 mg/dL; 95% CI: −10.97, −0.99), and lower mean triglyceride level (MD: −11.25 mg/dL; 95% CI: −21.83, −0.68) than the placebo group. Compared with placebo, the ephedrine-containing products showed better effects on weight loss and lipid profiles, whereas they caused increased heart rate. The ephedrine-containing products may be beneficial to obese or overweight patients; however, close monitoring is needed, especially heart rate monitoring

Gene Polymorphisms of the Renin-Angiotensin System and Bleeding Complications of Warfarin: Genetic-Based Machine Learning Models

Background: This study aimed to investigate the effects of genetic variants and haplotypes in the renin–angiotensin system (RAS) on the risk of warfarin-induced bleeding complications at therapeutic international normalized ratios (INRs). Methods: Four single nucleotide polymorphisms (SNPs) of AGT, two SNPs of REN, three SNPs of ACE, four SNPs of AGTR1, and one SNP of AGTR2, in addition to VKORC1 and CYP2C9 variants, were investigated. We utilized logistic regression and several machine learning methods for bleeding prediction. Results: The study included 142 patients, among whom 21 experienced bleeding complications. We identified a haplotype, H2 (TCG), carrying three SNPs of ACE (rs1800764, rs4341, and rs4353), which showed a significant relation with bleeding complications. After adjusting covariates, patients with H2/H2 experienced a 0.12-fold (95% CI 0.02–0.99) higher risk of bleeding complications than the others. In addition, G allele carriers of AGT rs5050 and A allele carriers of AGTR1 rs2640543 had 5.0- (95% CI 1.8–14.1) and 3.2-fold (95% CI 1.1–8.9) increased risk of bleeding complications compared with the TT genotype and GG genotype carriers, respectively. The AUROC values (mean, 95% CI) across 10 random iterations using five-fold cross-validated multivariate logistic regression, elastic net, random forest, support vector machine (SVM)–linear kernel, and SVM–radial kernel models were 0.732 (0.694–0.771), 0.741 (0.612–0.870), 0.723 (0.589–0.857), 0.673 (0.517–0.828), and 0.680 (0.528–0.832), respectively. The highest quartile group (≥75th percentile) of weighted risk score had approximately 12.0 times (95% CI 3.1–46.7) increased risk of bleeding, compared to the 25–75th percentile group, respectively. Conclusion: This study demonstrated that RAS-related polymorphisms, including the H2 haplotype of the ACE gene, could affect bleeding complications during warfarin treatment for patients with mechanical heart valves. Our results could be used to develop individually tailored intervention strategies to prevent warfarin-induced bleeding

Association between ABCA1 Gene Polymorphisms and Plasma Lipid Concentration: A Systematic Review and Meta-Analysis

Background: Although ABCA1 gene polymorphisms may be associated with the plasma lipid concentration, the literature has not shown a consistent pattern. In this study, we attempted to elucidate the association between the ABCA1 69C>T, 825V>I, and 230R>C polymorphisms and the plasma lipid concentration through a systematic review and meta-analysis. Methods: We selected studies published up to October 2020 in the PubMed, Web of Science, and Embase databases according to inclusion and exclusion criteria. The mean difference (MD) and 95% confidence interval (CI) were used to assess the relationship between the presence of ABCA1 69C>T, 825V>I, and 230R>C and plasma lipid levels. Meta-analysis was performed using Review Manager (version 5.3). Both Begg’s test and Egger’s regression test of the funnel plot were performed using R Studio software (version 3.6.0) to identify publication bias. Results: We analyzed the data on the ABCA1 69C>T polymorphism involving 14,843 subjects in 11 studies, 825V>I polymorphism involving 2580 subjects in 5 studies, and 230R>C polymorphism involving 4834 subjects in 4 studies. The T allele carriers in 69C>T, II carriers in 825V>I, and C carriers in 230R>C had lower high-density lipoprotein cholesterol levels; the MD (95% CI) was −0.05 mmol/L (95% CI: −0.09 to −0.01, p = 0.02), −0.05 mmol/L (95% CI: −0.09 to −0.00, p = 0.03), and −0.1 mmol/mL (95% CI: −0.12 to −0.07 mmol/L, p < 0.00001), respectively. In the case of 230R>C, the serum total cholesterol concentration of C carriers was significantly lower than that of RR carriers (−0.2 mmol/L, 95% CI: −0.3 to −0.11, p < 0.0001). Conclusion: This meta-analysis demonstrates that the ABCA1 69C>T, 825V>I, and 230R>C polymorphisms could affect the plasma lipid concentration. As the plasma lipid concentration may be related to various diseases, ABCA1 genotyping could be useful for the management of lipid levels

Effect of ITPA Polymorphism on Adverse Drug Reactions of 6-Mercaptopurine in Pediatric Patients with Acute Lymphoblastic Leukemia: A Systematic Review and Meta-Analysis

6-Mercaptopurine (6-MP) is a cornerstone of the maintenance regimen for pediatric acute lymphoblastic leukemia (ALL). Inosine triphosphate pyrophosphatase (ITPA) is considered a candidate pharmacogenetic marker that may affect metabolism and 6-MP-induced toxicities; however, the findings are inconsistent. Therefore, we attempted to evaluate the effect of ITPA 94C>A polymorphism on 6-MP-induced hematological toxicity and hepatotoxicity through a systematic review and meta-analysis. A literature search for qualifying studies was conducted using the PubMed, Web of Science, and Embase databases until October 2021. Overall, 10 eligible studies with 1072 pediatric ALL patients were included in this meta-analysis. The results indicated that ITPA 94C>A was significantly associated with 6-MP-induced neutropenia (OR 2.38, 95% CI: 1.56–3.62; p = 0.005) and hepatotoxicity (OR 1.98, 95% CI: 1.32–2.95; p = 0.0009); however, no significant association was found between the ITPA 94C>A variant and 6-MP-induced leukopenia (OR 1.75, 95% CI: 0.74–4.12; p = 0.20). This meta-analysis demonstrated that ITPA 94C>A polymorphism could affect 6-MP-induced toxicities. Our findings suggested that ITPA genotyping might help predict 6-MP-induced myelosuppression and hepatotoxicity

Association between Genetic Polymorphisms and Bleeding in Patients on Direct Oral Anticoagulants

Objectives: The purpose of our study is to investigate the effects of apolipoprotein B (APOB) and APOE gene polymorphisms on bleeding complications in patients receiving direct oral anticoagulants (DOACs). Methods: A total of 16 single nucleotide polymorphisms (SNPs) in 468 patients were genotyped. Six SNPs of ABCB1 (rs3842, rs1045642, rs2032582, rs1128503, rs3213619, and rs3747802), one SNP of CYP3A5 (rs776746), seven SNPs of APOB (rs1042034, rs2163204, rs693, rs679899, rs13306194, rs13306198, and rs1367117), and two SNPs of APOE (rs429358 and rs7412) were analyzed by a TaqMan genotyping assay. Multivariable logistic regression analysis with selected variables was performed for the construction of a risk scoring system. Two risk scoring systems were compared (demographic factors only vs. demographic factors and genetic factors). Results: In the multivariable analyses, two models were constructed; only demographic factors were included in Model I and both demographic factors and genetic factors in Model II. Rivaroxaban and anemia showed significant association with bleeding in both models. Additionally, ABCB1 rs3842 variant homozygote carriers (CC) and APOB rs13306198 variant allele carriers (AG, AA) had a higher risk of bleeding risk compared with that of wild-type allele carriers (TT, TC) and wild-type homozygote carriers (GG), respectively. Whereas the area under the receiver operating characteristic curve (AUROC) value using demographic factors only was 0.65 (95% confidence interval (CI): 0.56–0.74), the AUROC increased to 0.72 by adding genetic factors (95% CI: 0.65–0.80). The predicted bleeding risks of bleeding in patients with 0, 1, 2, 3, 4, 5, 6, 7 and 8 points from the logistic regression curve were 0.8%, 2.0%, 5.4%, 5.2%, 12.5%, 26.9%, 47.0%, 64.3% and 82.3%, respectively. Conclusions: The study results can be used for enhancing individualized treatment strategies in patients taking DOACs, helping clinicians predict the bleeding risk