A scalable and robust variance components method reveals insights into the architecture of gene-environment interactions underlying complex traits.

Understanding the contribution of gene-environment interactions (GxE) to complex trait variation can provide insights into disease mechanisms, explain sources of heritability, and improve genetic risk prediction. While large biobanks with genetic and deep phenotypic data hold promise for obtaining novel insights into GxE, our understanding of GxE architecture in complex traits remains limited. We introduce a method to estimate the proportion of trait variance explained by GxE (GxE heritability) and additive genetic effects (additive heritability) across the genome and within specific genomic annotations. We show that our method is accurate in simulations and computationally efficient for biobank-scale datasets. We applied our method to common array SNPs (MAF ≥1%), fifty quantitative traits, and four environmental variables (smoking, sex, age, and statin usage) in unrelated white British individuals in the UK Biobank. We found 68 trait-E pairs with significant genome-wide GxE heritability (p<0.05/200) with a ratio of GxE to additive heritability of ≈6.8% on average. Analyzing ≈8 million imputed SNPs (MAF ≥0.1%), we documented an approximate 28% increase in genome-wide GxE heritability compared to array SNPs. We partitioned GxE heritability across minor allele frequency (MAF) and local linkage disequilibrium (LD) values, revealing that, like additive allelic effects, GxE allelic effects tend to increase with decreasing MAF and LD. Analyzing GxE heritability near genes highly expressed in specific tissues, we find significant brain-specific enrichment for body mass index (BMI) and basal metabolic rate in the context of smoking and adipose-specific enrichment for waist-hip ratio (WHR) in the context of sex.

Evaluation of the effect of modafinil on the pharmacokinetics of encorafenib and binimetinib in patients with BRAF V600-mutant advanced solid tumors.

BACKGROUND: A clinical drug-drug interaction (DDI) study was designed to evaluate the effect of multiple doses of modafinil, a moderate CYP3A4 inducer at a 400 mg QD dose, on the multiple oral dose pharmacokinetics (PK) of encorafenib and its metabolite, LHY746 and binimetinib and its metabolite, AR00426032. METHODS: This study was conducted in patients with BRAF V600-mutant advanced solid tumors. Treatment of 400 mg QD modafinil was given on Day 15 through Day 21. Encorafenib 450 mg QD and binimetinib 45 mg BID were administered starting on Day 1. PK sampling was conducted from 0 to 8 h on Day 14 and Day 21. Exposure parameters were calculated for each patient by noncompartmental analysis and geometric least-squares mean ratio. Corresponding 90% confidence intervals were calculated to estimate the magnitude of effects. RESULTS: Among 11 PK evaluable patients, encorafenib Cmax and AUClast were decreased in presence of steady-state modafinil by 20.2% and 23.8%, respectively. LHY746 exposures were not substantially changed in the presence of steady-state modafinil. CONCLUSION: The results from this clinical study indicate modafinil 400 mg QD had a weak effect on encorafenib PK. Based on these results, encorafenib can be coadministered with a moderate CYP3A4 inducer without dosing adjustment. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03864042, registered 6 March 2019.

[Prevention of drug iatrogenicity]. / Prévention de la «iatrogénie médicamenteuse¼.

Adverse events related to drug therapy are a major cause of iatrogenicity. They are responsible of increased morbidity, leading to hospitalization, sometimes in emergency, and mortality, not only in ambulatory care but also during hospitalization itself. Causes are multiple : among them, confusion leading to an erroneous drug administration, mistakes regarding dosage, risks associated to self-medication, drug-drug interactions or even food-drug interactions. Elderly population is exposed to an increased incidence of drug iatrogenicity because older patients cumulate numerous risk factors, especially polypharmacy and cognitive disorders. Prevention of drug iatrogenicity is a key objective from a public health point of view. Preventive measures should target the prescriber (physician), the dispenser (pharmacist), the user (patient) and the supplier (pharmaceutical industry).

Les manifestations indésirables liées à la prise des médicaments représentent une cause non négligeable d'iatrogénie. Elles sont responsables d'une morbidité, amenant des hospitalisations parfois en urgence, voire d'une mortalité, non seulement en ambulatoire mais aussi au sein même de l'hôpital. Les causes sont multiples. Citons, notamment, la confusion aboutissant à la prise d'un médicament erroné, les erreurs dans la posologie, les risques liés à l'auto-médication, les interactions médicamenteuses, ou encore, les interactions aliments- médicaments. La population âgée est particulièrement exposée car elle cumule nombre de facteurs de risque, dont la polymédication et les troubles cognitifs. La prévention de la iatrogénie médicamenteuse est donc un objectif prioritaire dans le domaine de la pharmacothérapie. Les mesures préventives devraient cibler le prescripteur (médecin), le délivreur (pharmacien), l'utilisateur (patient) et le fournisseur (industrie pharmaceutique).

DAS-DDI: A dual-view framework with drug association and drug structure for drug-drug interaction prediction.

In drug development and clinical application, drug-drug interaction (DDI) prediction is crucial for patient safety and therapeutic efficacy. However, traditional methods for DDI prediction often overlook the structural features of drugs and the complex interrelationships between them, which affect the accuracy and interpretability of the model. In this paper, a novel dual-view DDI prediction framework, DAS-DDI is proposed. Firstly, a drug association network is constructed based on similarity information among drugs, which could provide rich context information for DDI prediction. Subsequently, a novel drug substructure extraction method is proposed, which could update the features of nodes and chemical bonds simultaneously, improving the comprehensiveness of the feature. Furthermore, an attention mechanism is employed to fuse multiple drug embeddings from different views dynamically, enhancing the discriminative ability of the model in handling multi-view data. Comparative experiments on three public datasets demonstrate the superiority of DAS-DDI compared with other state-of-the-art models under two scenarios.

MPHGCL-DDI: Meta-Path-Based Heterogeneous Graph Contrastive Learning for Drug-Drug Interaction Prediction.

The combinatorial therapy with multiple drugs may lead to unexpected drug-drug interactions (DDIs) and result in adverse reactions to patients. Predicting DDI events can mitigate the potential risks of combinatorial therapy and enhance drug safety. In recent years, deep models based on heterogeneous graph representation learning have attracted widespread interest in DDI event prediction and have yielded satisfactory results, but there is still room for improvement in prediction performance. In this study, we proposed a meta-path-based heterogeneous graph contrastive learning model, MPHGCL-DDI, for DDI event prediction. The model constructs two contrastive views based on meta-paths: an average graph view and an augmented graph view. The former represents that there are connections between drugs, while the latter reveals how the drugs connect with each other. We defined three levels of data augmentation schemes in the augmented graph view and adopted a combination of three losses in the model training phase: multi-relation prediction loss, unsupervised contrastive loss and supervised contrastive loss. Furthermore, the model incorporates indirect drug information, protein-protein interactions (PPIs), to reveal latent relations of drugs. We evaluated MPHGCL-DDI on three different tasks of two datasets. Experimental results demonstrate that MPHGCL-DDI surpasses several state-of-the-art methods in performance.

Doses Evaluated in Clinical Pharmacology Studies Investigating the Effect of Intrinsic and Extrinsic Factors on PK and Safety: Case Examples from Approved Drug Development Programs.

Dose selection for investigations of intrinsic and extrinsic factors of pharmacokinetic variability as well as safety is a challenging question in the early clinical stage of drug development. The dose of an investigational product is chosen considering the compound information available to date, feasibility of the assessments, regulatory requirements, and the intent to maximize information for later regulatory submission. This review selected 37 programs as case examples of recently approved drugs to explore the doses selected with focus on studies of drug interaction, renal and hepatic impairment, food effect and concentration-QTc assessment.The review found that regulatory agencies may consider alternative approaches if justified and safe as illustrated in these examples. It is thus recommendable to use the first in human trial as an opportunity to assess QT-prolongation and drug interactions using probes or endogenous markers while maximizing the DDI potential, increasing sensitivity and ensuring safety. Early understanding of dose proportionality assists dose finding and simple and fast to conduct DDI study designs are advantageous. Single dose impairment studies despite non-proportional/time-dependent PK are often acceptability.Overall, the early understanding of the drug's safety profile is essential to ensure the safety of doses selected while preventing clinical trials with unnecessary exposure when using high doses or multiple doses. The information collected in this retrospective survey is a good reminder to tailor the early clinical program to the profile and needs of the molecule and consider regulatory opportunities to streamline the development path.

Assessing the benefit-risk balance of drugs. Some lessons from the COVID pandemic.

INTRODUCTION: Drug efficacy and effectiveness are assessed respectively through clinical trials and pharmaco-epidemiological studies. However, relative and absolute benefits of drugs are distinct measures that must be considered in relation to the baseline risk of disease incidence, complication or progression. On the other hand, adverse drug reactions are independent of the basic risk but depend on the characteristics of the population treated. Given these prerequisites, how can we balance the benefits and risks of drugs? AREAS COVERED: We use the example of therapeutics evaluated during Covid to describe how assessing the benefit-risk balance of drugs is a complex process. EXPERT OPINION: Clinical trials are not designed to identify rare adverse events, underscoring the necessity for a pharmacovigilance system. Evaluating the balance between the benefits and risks of drugs is an ongoing process, demanding the simultaneous analysis of data from clinical trials, potential drug-drug interactions, pharmacovigilance monitoring and pharmaco-epidemiological studies, to identify potential safety concerns. In addition, pharmacologists must play a major role in educating the general public about drugs, aiding in the accurate interpretation of the benefit-risk balance and preventing misinformation.

Unravelling the complexities of non-alcoholic steatohepatitis: The role of metabolism, transporters, and herb-drug interactions.

Nonalcoholic fatty liver disease (NAFLD) is a mainstream halting liver disease with high prevalence in North America, Europe, and other world regions. It is an advanced form of NAFLD caused by the amassing of fat in the liver and can progress to the more severe form known as non-alcoholic steatohepatitis (NASH). Until recently, there was no authorized pharmacotherapy reported for NASH, and to improve the patient's metabolic syndrome, the focus is mainly on lifestyle modification, weight loss, ensuring a healthy diet, and increased physical activity; however, the recent approval of Rezdiffra (Resmetirom) by the US FDA may change this narrative. As per the reported studies, there is an increased articulation of uptake and efflux transporters of the liver, including OATP and MRP, in NASH, leading to changes in the drug's pharmacokinetic properties. This increase leads to alterations in the pharmacokinetic properties of drugs. Furthermore, modifications in Cytochrome P450 (CYP) enzymes can have a significant impact on these properties. Xenobiotics are metabolized primarily in the liver and constitute liver enzymes and transporters. This review aims to delve into the role of metabolism, transport, and potential herb-drug interactions in the context of NASH.

Comorbidity and concomitant medication use in an integrase strand transfer inhibitor naïve cohort on first-line dolutegravir-based antiretroviral therapy.

Introduction: people living with HIV/AIDS using antiretroviral therapy sometimes present with comorbid conditions or co-infections. This could lead to an increased risk of drug interactions due to the concomitant use of drugs. The aim of the study was to explore the overall impact of dolutegravir on such comorbidities and the effect of concomitant medication on the safety and efficacy of dolutegravir. Methods: data was collected using a survey questionnaire and a retrospective review of medical records of a prospective study sample. Medical records were retrospectively reviewed for up to 12 months after dolutegravir initiation. Concomitantly used drugs and supplements that were identified to have a potential interaction with dolutegravir were further characterized. Descriptive and summary statistics were used to describe the data, t-tests were performed on blood glucose levels and cross-tabulations were done on some variables. Results: of the 461 participants enrolled into the study, 172 (37.3%) and 54 (11.7%) experienced comorbidity and coinfection respectively. More than 50% of the participants used concomitant medicines. Metformin use led to increased blood glucose levels (p=0.009); participants on rifampicin (n=8) received an additional daily dose of dolutegravir. Virological outcomes in participants on sodium valproate (n=2) and St John´s wort (n=1) did not show safety concerns, whilst 3 dolutegravir discontinuations were observed in participants using supplements and antacids containing divalent cations. Conclusion: even though dolutegravir was safe and effective in the study population, with possible drug interactions leading to treatment discontinuations in only 3(0.7%) participants, further investigation into dolutegravir-induced hyperglycemia needs investigation.

Accurate prediction of drug combination risk levels based on relational graph convolutional network and multi-head attention.

BACKGROUND: Accurately identifying the risk level of drug combinations is of great significance in investigating the mechanisms of combination medication and adverse reactions. Most existing methods can only predict whether there is an interaction between two drugs, but cannot directly determine their accurate risk level. METHODS: In this study, we propose a multi-class drug combination risk prediction model named AERGCN-DDI, utilizing a relational graph convolutional network with a multi-head attention mechanism. Drug-drug interaction events with varying risk levels are modeled as a heterogeneous information graph. Attribute features of drug nodes and links are learned based on compound chemical structure information. Finally, the AERGCN-DDI model is proposed to predict drug combination risk level based on heterogenous graph neural network and multi-head attention modules. RESULTS: To evaluate the effectiveness of the proposed method, five-fold cross-validation and ablation study were conducted. Furthermore, we compared its predictive performance with baseline models and other state-of-the-art methods on two benchmark datasets. Empirical studies demonstrated the superior performances of AERGCN-DDI. CONCLUSIONS: AERGCN-DDI emerges as a valuable tool for predicting the risk levels of drug combinations, thereby aiding in clinical medication decision-making, mitigating severe drug side effects, and enhancing patient clinical prognosis.

Icaritin exhibits potential drug-drug interactions through the inhibition of human UDP-glucuronosyltransferase in vitro.

Icaritin is a prenylflavonoid derivative of the genus Epimedium (Berberidaceae) and has a variety of pharmacological actions. Icaritin is approved by the National Medical Products Administration as an anticancer drug that exhibits efficacy and safety advantages in patients with hepatocellular carcinoma cells. This study aimed to evaluate the inhibitory effects of icaritin on UDP-glucuronosyltransferase (UGT) isoforms. 4-Methylumbelliferone (4-MU) was employed as a probe drug for all the tested UGT isoforms using in vitro human liver microsomes (HLM). The inhibition potentials of UGT1A1 and 1A9 in HLM were further tested by employing 17ß-estradiol (E2) and propofol (PRO) as probe substrates, respectively. The results showed that icaritin inhibits UGT1A1, 1A3, 1A4, 1A7, 1A8, 1A10, 2B7, and 2B15. Furthermore, icaritin exhibited a mixed inhibition of UGT1A1, 1A3, and 1A9, and the inhibition kinetic parameters (Ki) were calculated to be 3.538, 2.117, and 0.306 (µM), respectively. The inhibition of human liver microsomal UGT1A1 and 1A9 both followed mixed mechanism, with Ki values of 2.694 and 1.431 (µM). This study provides supporting information for understanding the drug-drug interaction (DDI) potential of the flavonoid icaritin and other UGT-metabolized drugs in clinical settings. In addition, the findings provide safety evidence for DDI when liver cancer patients receive a combination therapy including icaritin.

Factors influencing serum concentrations of levetiracetam in dogs with epilepsy.

BACKGROUND: Factors affecting serum concentrations of levetiracetam in dogs are unknown and could affect the efficacy of levetiracetam in controlling seizures in dogs with epilepsy. HYPOTHESIS/OBJECTIVES: Higher PO doses of levetiracetam will be needed in dogs to achieve serum concentrations shown to be effective in humans. Determine factors that could influence serum levetiracetam concentrations and justify dose adjustment in some epileptic dogs. ANIMALS: Sixty-nine client-owned dogs with epilepsy treated with levetiracetam alone or in combination, based on 127 trough serum concentration measurements of levetiracetam. METHODS: Retrospective cohort study. Linear mixed models were used to assess the effect of patient signalment and concurrent drug administration on serum concentrations of levetiracetam and the effect of serum concentration of levetiracetam on seizure frequency reduction. RESULTS: The PO dose of levetiracetam significantly explained changes in serum levetiracetam concentration, and this causal link was stronger with monotherapy (R2 = 0.59, P < .001). Phenobarbital significantly decreased serum levetiracetam concentration in a dose dependent manner (R2 = 0.30, P = .003). Based on our model, a levetiracetam dosage of 99-216 mg/kg/day is necessary to obtain a serum levetiracetam concentration of 20 µg/mL when used alone or concurrently with 7 mg/kg/day of phenobarbital. No other factors were found to influence serum levetiracetam concentrations. No therapeutic range could be identified. CONCLUSION AND CLINICAL IMPORTANCE: Our data suggest that a dosage of 99-216 mg/kg/day of levetiracetam is needed to achieve a serum concentration known to be therapeutically effective in humans, especially when administered concomitantly with phenobarbital.

3D spheroid HepaRG and fluorescent biphasic tracer for CYP3A4-mediated antibiotic interaction monitoring in sepsis.

Cytochrome P450 3A4 (CYP3A4) is a crucial enzyme in the metabolism of xenobiotics, particularly in drug metabolism interactions (DDIs), making it a significant factor in clinical drug use. However, current assay techniques are both laborious and costly, making it difficult to construct a high-throughput monitoring method that can be used in conjunction with the clinic. This poses certain safety hazards for drug combination. Therefore, it is crucial to develop a synchronized monitoring method for the inhibition and induction of CYP3A4. In this study, we utilized 3D culture technology to develop a HepaRG cells spheroid model. The CYP450 and transporter expression, the albumin secretion, and urea synthesis capacity characteristics were analyzed. The NEN probe was utilized as a tracer molecule for CYP3A4. The fluorescence intensity of metabolites was characterized by laser confocal technique to determine the inhibition and expression of CYP3A4 in the HepaRG cell spheroid model by the antibiotics for sepsis. The results indicate that the HepaRG sphere model successfully possessed the physiological phenotype of the liver, which could be used for drug interaction monitoring. Through positive drug testing, NEN probe was able to achieve bidirectional characterization of CYP3A4 induction and inhibition. The monitoring method described in this paper was successfully applied to drug interaction monitoring of commonly used antibiotics in sepsis patients, which is a convenient and rapid monitoring method. The proposed method offers a new strategy for monitoring CYP3A4-mediated drug-drug interactions with a high-throughput assay, which will help to improve the safety of clinical drug combination.

Screening indicators to evaluate the clinical significance of drug-drug interactions in polypharmacy among older adults with psychiatric disorders: a delphi study.

BACKGROUND: Polypharmacy is common in older adults with psychiatric disorders, but no consensus has reached about the reliable indicators evaluating the benefits and risks of drug-drug interactions (DDIs) in polypharmacy. We aimed to identify indicators suitable for evaluating the clinical significance of DDIs in polypharmacy in older adults with psychiatric disorders. METHODS: The online tools were used to distribute and collect the questionnaires. The Delphi method was applied to analyze experts' opinions. The degree of authority and coordination of experts were analyzed using the coefficient of variation, coefficient of coordination, expert's judgment factor, familiarity with the study content factor, and Kendall coordination coefficient. Statistical analysis was conducted using the IBM SPSS® Statistics Package version 26.0. RESULTS: After three rounds of expert consultation, five primary and eleven secondary indicators were identified. The primary "pharmacodynamic indicator" included "severity of adverse drug reactions", "duration of adverse drug reaction", "symptom relief", "time to onset of symptomatic relief", "number of days in hospital", and "duration of medication". The secondary "pharmacokinetic indicator" contained "dosage administered" and "dosing intervals". The primary "patient tolerance indicator" contained one secondary indicator of "patient tolerability". The primary indicator "patient adherence" contained one secondary indicator of "patient adherence to medication". The primary indicator "cost of drug combination" contained one secondary indicator of "readmission". These indicators were used to determine the clinical significance of DDIs during polypharmacy. CONCLUSIONS: The clinical significance of drug combinations should be taken into account when polypharmacy is used in the elderly. The five primary indicators and eleven secondary indicators might be preferred to evaluate their risks and benefits. Medication management in this population requires a multidisciplinary team, in which nurses play a key role. Future research should focus on how to establish efficient multidisciplinary team workflows and use functional factors to assess DDIs in polypharmacy for psychiatric disorders.

Research on the mechanism of Guanyu Zhixie Granule in intervening gastric ulcers in rats based on network pharmacology and multi-omics.

Objective: Guanyu Zhixie Granule (GYZXG) is a traditional Chinese medicine compound with definite efficacy in intervening in gastric ulcers (GUs). However, the effect mechanisms on GU are still unclear. This study aimed to explore its mechanism against GU based on amalgamated strategies. Methods: The comprehensive chemical characterization of the active compounds of GYZXG was conducted using UHPLC-Q/TOF-MS. Based on these results, key targets and action mechanisms were predicted through network pharmacology. GU was then induced in rats using anhydrous ethanol (1 mL/200 g). The intervention effects of GYZXG on GU were evaluated by measuring the inhibition rate of GU, conducting HE staining, and assessing the levels of IL-6, TNF-α, IL-10, IL-4, Pepsin (PP), and epidermal growth factor (EGF). Real-time quantitative PCR (RT-qPCR) was used to verify the mRNA levels of key targets and pathways. Metabolomics, combined with 16S rRNA sequencing, was used to investigate and confirm the action mechanism of GYZXG on GU. The correlation analysis between differential gut microbiota and differential metabolites was conducted using the spearman method. Results: For the first time, the results showed that nine active ingredients and sixteen targets were confirmed to intervene in GU when using GYZXG. Compared with the model group, GYZXG was found to increase the ulcer inhibition rate in the GYZXG-M group (p < 0.05), reduce the levels of IL-6, TNF-α, PP in gastric tissue, and increase the levels of IL-10, IL-4, and EGF. GYZXG could intervene in GU by regulating serum metabolites such as Glycocholic acid, Epinephrine, Ascorbic acid, and Linoleic acid, and by influencing bile secretion, the HIF-1 signaling pathway, and adipocyte catabolism. Additionally, GYZXG could intervene in GU by altering the gut microbiota diversity and modulating the relative abundance of Bacteroidetes, Bacteroides, Verrucomicrobia, Akkermansia, and Ruminococcus. The differential gut microbiota was strongly associated with serum differential metabolites. KEGG enrichment analysis indicated a significant role of the HIF-1 signaling pathway in GYZXG's intervention on GU. The changes in metabolites within metabolic pathways and the alterations in RELA, HIF1A, and EGF mRNA levels in RT-qPCR experiments provide further confirmation of this result. Conclusion: GYZXG can intervene in GU induced by anhydrous ethanol in rats by regulating gut microbiota and metabolic disorders, providing a theoretical basis for its use in GU intervention.

Effect of eugenol on cytochrome P450 1A2, 2C9, 2D6, and 3A4 activity in human liver microsomes.

This study aimed to provide an understanding of the influence of eugenol on CYP1A2, 2C9, 2D6, and 3A4 in human liver microsomes (HLM). Specific substrate for CYP1A2, 2C9, 2D6, and 3A4 were incubated in HLM with or without eugenol. The formation of their respective metabolites was assessed with HPLC analytical methods. Eugenol at 1, 10 and 100 µM levels inhibited the activity of CYP1A2 and CYP2C9 by 23.38 %, 23.57 %, 39.80 % and 62.82 %, 63.27 %, 67.70 % respectively. While, CYP2D6 and CYP3A4 activity was decreased by 40.70 %, 45.88 %, 62.68 % and 37.41 %, 42.58 % and 67.86 % at 1, 10 and 100 µM eugenol level respectively. The IC50 value of eugenol for CYP2D6 and CYP3A4 was calculated as 11.09 ± 3.49 µM and 13.48 ± 3.86 µM respectively. Potential herb-drug interactions was noted when eugenol is administered simultaneously with medications metabolized by these enzymes, most notably CYP2C9, CYP2D6 and CYP3A4.

Hypertensive Crisis Associated with Serotonin Syndrome Following Linezolid Administration: Report of Two Cases.

INTRODUCTION: Serotonin syndrome is a potentially life-threatening condition that can occur as a result of the therapeutic use of serotonergic medications or drug interaction. In this study, we describe two cases of serotonin syndrome-associated hypertensive crisis following linezolid use. CASE PRESENTATION: The first patient was a 52-year-old female who was admitted due to a diabetic foot infection and pneumonia associated with a decreased consciousness level. Serotonin syndrome occurred 24 hours after starting the linezolid use. Resistant hypertension was the main hemodynamic finding. It could not be controlled with amlodipine, valsartan, prazosin, and nitroglycerin infusion. Resistant hypertension and other symptoms of serotonin syndrome were resolved about 48 hours after discontinuation of linezolid use. The second case was a man with a history of kidney transplant, diabetes, and hypertension. He was admitted to the ICU due to severe COVID-19 broad-spectrum antibiotics [linezolid, cefepime], and remdesivir was initiated. Following intubation, continuous infusion of fentanyl was used for sedation. Within 24 hours after fentanyl and linezolid initiation, severe agitation, eye clonus, hyperreflexia, hypertension [160-186 /90-110 mmHg], and tachycardia [>100/min] were noted. With the possible diagnosis of serotonin syndrome, fentanyl was discontinued, and morphine was initiated. The patient's symptoms improved 48 hours after discontinuation of fentanyl. CONCLUSION: Both of the patients had a history of controlled hypertension. However, serotonin syndrome occurred following the use of linezolid and concomitant/recent use of serotonergic agents. A thorough evaluation of the patient's medical history and current situation can help clinicians prevent this syndrome in critically ill patients.

Minimal involvement of P-gp and BCRP in oral absorption of ensitrelvir, an oral SARS-CoV-2 3C-like protease inhibitor, in a non-clinical investigation.

P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are important transporters causing drug-drug interaction (DDI). Here, we investigated the involvement of P-gp and BCRP in the oral absorption of ensitrelvir in non-clinical studies and estimated the DDI risk mediated by P-gp and BCRP inhibition in humans. Although ensitrelvir is an in vitro P-gp and BCRP substrate, it demonstrated high bioavailability in rats and monkeys after oral administration. Plasma exposures of ensitrelvir following oral administration were comparable in wild type (WT) and Bcrp (-/-) mice. On the other hand, the area under the plasma concentration-time curve (AUC) ratio of ensitrelvir in the Mdr1a/1b (-/-) mice to the WT mice was 1.92, indicating that P-gp, but not BCRP, was involved in the oral absorption of ensitrelvir. Based on our previous retrospective analyses, such a low AUC ratio (<3) in the Mdr1a/1b (-/-) mice indicates a minimal impact of P-gp on the oral absorption in humans. In conclusion, our studies demonstrate that the involvement of both P-gp and BCRP in the oral absorption of ensitrelvir is minimal, and suggest that ensitrelvir has a low risk for DDIs mediated by P-gp and BCRP inhibition in humans.

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.

Paralytic ileus in a patient on clozapine therapy showing an inverted clozapine/norclozapine ratio after switching valproic acid to carbamazepine: a case report.

This case report examines the possible correlation between the clozapine/norclozapine ratio and the occurrence of constipation and paralytic ileus. We present the case of a 42-year-old patient diagnosed with schizoaffective disorder undergoing clozapine therapy. Despite intensive treatment with clozapine, haloperidol, valproic acid and biweekly electroconvulsive therapy sessions for over a year, florid psychotic symptoms and fluctuating mood swings persisted. Therefore, valproic acid was replaced by carbamazepine, a potent inducer of several CYP450-enzymes. To maintain clozapine plasma levels, fluvoxamine, a CYP1A2-inhibitor, was introduced at a dose of 25 mg before this switch. After addition of carbamazepine, there was a significant decline in clozapine levels, necessitating an increase in fluvoxamine dosage to 50 mg. Five weeks later the patient was admitted to a general hospital with a diagnosis of paralytic ileus. Treatment with enemas proved effective. Drug concentration analysis revealed a 2.5-fold increase in norclozapine levels in the weeks preceding hospital admission, resulting in an inverted clozapine/norclozapine ratio. Treatment with clozapine, carbamazepine and fluvoxamine was continued as the patient demonstrated clinical improvement on carbamazepine. Concurrently, an intensive laxative regimen was initiated. Two weeks later, the patient was readmitted to the general hospital due to suspected paralytic ileus and faecal vomiting, once again displaying an inverted clozapine/norclozapine ratio. We discuss potential mechanisms contributing to the occurrence of the paralytic ileus in this patient, including the antagonism of muscarinic M3 receptors by both clozapine and norclozapine, as well as the agonism of delta-opioid receptors by norclozapine. This case highlights the potential significance of both the clozapine/norclozapine ratio and absolute norclozapine levels as risk factors for constipation and paralytic ileus in patients on clozapine therapy.