Mechanisms Of Drug Interactions Research Articles

Pirtobrutinib: First Non-covalent Tyrosine Kinase Inhibitor for Treating Relapsed or Refractory Mantle Cell Lymphoma in Adults.

Mantle Cell Lymphoma (MCL) is an aggressive subtype of Non-hodgkin's Lymphoma (NHL). Bruton Tyrosine Kinase (BTK) is a non receptor tyrosine kinase, and is one of the therapeutic targets for B-cell-driven malignancies. Approved covalent BTK inhibitors such as ibrutinib, acalabrutinib, and zanubrutinib are associated with treatment limitations due to off-target side effects and the development of C481 substitution resistance mutations. Pirtobrutinib was approved by the US FDA on January 27, 2023, for the treatment of relapsed or refractory mantle cell lymphoma, including the resistance to covalent BTK inhibitors. In this perspective, physicochemical properties, synthesis, dosage and administration, mechanism of action, pharmacodynamics, pharmacokinetics, drug interactions, and treatment-emergent adverse events of pirtobrutinib are discussed.

Enhanced Sampling Molecular Dynamics Simulations Reveal Transport Mechanism of Glycoconjugate Drugs through GLUT1.

Glucose transporters GLUT1 belong to the major facilitator superfamily and are essential to human glucose uptake. The overexpression of GLUT1 in tumor cells designates it as a pivotal target for glycoconjugate anticancer drugs. However, the interaction mechanism of glycoconjugate drugs with GLUT1 remains largely unknown. Here, we employed all-atom molecular dynamics simulations, coupled to steered and umbrella sampling techniques, to examine the thermodynamics governing the transport of glucose and two glycoconjugate drugs (i.e., 6-D-glucose-conjugated methane sulfonate and 6-D-glucose chlorambucil) by GLUT1. We characterized the specific interactions between GLUT1 and substrates at different transport stages, including substrate recognition, transport, and releasing, and identified the key residues involved in these procedures. Importantly, our results described, for the first time, the free energy profiles of GLUT1-transporting glycoconjugate drugs, and demonstrated that H160 and W388 served as important gates to regulate their transport via GLUT1. These findings provide novel atomic-scale insights for understanding the transport mechanism of GLUT1, facilitating the discovery and rational design of GLUT1-targeted anticancer drugs.

Targeting Colorectal Cancer: Unravelling the Transcriptomic Impact of Cisplatin and High-THC Cannabis Extract.

Cisplatin and other platinum-derived chemotherapy drugs have been used for the treatment of cancer for a long time and are often combined with other medications. Unfortunately, tumours often develop resistance to cisplatin, forcing scientists to look for alternatives or synergistic combinations with other drugs. In this work, we attempted to find a potential synergistic effect between cisplatin and cannabinoid delta-9-THC, as well as the high-THC Cannabis sativa extract, for the treatment of HT-29, HCT-116, and LS-174T colorectal cancer cell lines. However, we found that combinations of the high-THC cannabis extract with cisplatin worked antagonistically on the tested colorectal cancer cell lines. To elucidate the mechanisms of drug interactions and the distinct impacts of individual treatments, we conducted a comprehensive transcriptomic analysis of affected pathways within the colorectal cancer cell line HT-29. Our primary objective was to gain a deeper understanding of the underlying molecular mechanisms associated with each treatment modality and their potential interactions. Our findings revealed an antagonistic interaction between cisplatin and high-THC cannabis extract, which could be linked to alterations in gene transcription associated with cell death (BCL2, BAD, caspase 10), DNA repair pathways (Rad52), and cancer pathways related to drug resistance.

Investigation of the drug–drug interaction and incompatibility mechanism between Aconitum carmichaelii Debx and Pinellia ternata (Thunb.) Breit

Ethnopharmacological relevanceThe combination of Aconitum carmichaelii Debx (Chuanwu, CW) and Pinellia ternata (Thunb.) Breit (Banxia, BX) forms an herbal pair within the eighteen incompatible medicaments (EIM), indicating that BX and CW are incompatible. However, the scientific understanding of this incompatibility mechanism, especially the corresponding drug–drug interaction (DDI), remains complex and unclear. Aim of the studyThis study aims to explain the DDI and potential incompatibility mechanism between CW and BX based on pharmacokinetics and cocktail approach. Materials and methodsUltraperformance liquid chromatography–tandem mass spectrometry methods were established for pharmacokinetics and cocktail studies. To explore the DDI between BX and CW, in the pharmacokinetics study, 10 compounds were determined in rat plasma after administering CW and BX–CW herbal pair extracts. In the cocktail assay, the pharmacokinetic parameters of five probe substrates were utilized to assess the influence of BX on cytochrome P450 (CYP) isoenzyme (dapsone for CYP3A4, phenacetin for CYP1A2, dextromethorphan for CYP2D6, tolbutamide for CYP2C9, and omeprazole for CYP2C19). Finally, the DDI and incompatibility mechanism of CW and BX were integrated to explain the rationality of EIM theory. ResultsBX not only enhances the absorption of aconitine and benzoylaconine but also accelerates the metabolism of mesaconitine, benzoylmesaconine, songorine, and fuziline. Moreover, BX affects the activity of CYP enzymes, which regulate the metabolism of toxic compounds. ConclusionsBX altered the activity of CYP enzymes, consequently affecting the metabolism of toxic compounds from CW. This incompatibility mechanism may be related to the increased absorption of these toxic compounds in vivo.

MFSynDCP: multi-source feature collaborative interactive learning for drug combination synergy prediction

Drug combination therapy is generally more effective than monotherapy in the field of cancer treatment. However, screening for effective synergistic combinations from a wide range of drug combinations is particularly important given the increase in the number of available drug classes and potential drug-drug interactions. Existing methods for predicting the synergistic effects of drug combinations primarily focus on extracting structural features of drug molecules and cell lines, but neglect the interaction mechanisms between cell lines and drug combinations. Consequently, there is a deficiency in comprehensive understanding of the synergistic effects of drug combinations. To address this issue, we propose a drug combination synergy prediction model based on multi-source feature interaction learning, named MFSynDCP, aiming to predict the synergistic effects of anti-tumor drug combinations. This model includes a graph aggregation module with an adaptive attention mechanism for learning drug interactions and a multi-source feature interaction learning controller for managing information transfer between different data sources, accommodating both drug and cell line features. Comparative studies with benchmark datasets demonstrate MFSynDCP's superiority over existing methods. Additionally, its adaptive attention mechanism graph aggregation module identifies drug chemical substructures crucial to the synergy mechanism. Overall, MFSynDCP is a robust tool for predicting synergistic drug combinations. The source code is available from GitHub at https://github.com/kkioplkg/MFSynDCP.

Mitapivat: A Novel Treatment of Hemolytic Anemia in Adults with Pyruvate Kinase Deficiency.

Mitapivat is an orally bioavailable small molecule allosteric activator of pyruvate kinase. It was approved by the US FDA on February 17, 2022, and the European Union in November 2022 for the treatment of hemolytic anemia in adult patients with pyruvate kinase deficiency. In this short perspective, physicochemical properties, synthesis, dosage and administration, mechanism of action, pharmacodynamics, pharmacokinetics, drug interactions, and adverse reactions of mitapivat are described.

First Approval of Elacestrant as a Selective Estrogen Receptor Degrader for the Treatment of Metastatic Breast Cancer.

Elacestrant was approved by the US FDA on January 27, 2023, for treating postmenopausal women or adult men with estrogen receptor (ER)-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression prior to using at least one line of endocrine therapy. In this short perspective, physicochemical properties, dosage and administration, mechanism of action, pharmacodynamics, pharmacokinetics, drug interaction, and treatment-related adverse reactions of elacestrant are summarized.

Futibatinib: A Potent and Irreversible Inhibitor of Fibroblast Growth Factor Receptors for Treatment of the Bile Duct Cancer.

Cholangiocarcinoma is a rare type of cancer. Futibatinib is an irreversible, potent, selective inhibitor of fibroblast growth factor receptors (FGFR 1-4). On September 30, 2022, the US FDA first approved futibatinib to treat adult patients with bile duct cancer whose disease is unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma harboring fibroblast growth factor receptor 2 (FGFR2</i>) gene mutations or other classes of rearrangements. The approval of this medicine was based on phase 3 clinical trial results including an overall response rate (ORR) of 42% and a duration of response (DoR) of 9.7 months. This short perspective summarizes Futibatinib's synthesis, physicochemical properties, dosage, route of administration, mechanism of action, binding mode, pharmacodynamics, pharmacokinetics, drug interactions, adverse events, and possible mechanism of resistance.

Electroanalysis in Pharmacogenomic Studies: Mechanisms of Drug Interaction with DNA.

The review discusses electrochemical methods for analysis of drug interactions with DNA. The electroanalysis method is based on the registration of interaction-induced changes in the electrochemical oxidation potential of heterocyclic nitrogenous bases in the DNA molecule and in the maximum oxidation current amplitude. The mechanisms of DNA-drug interactions can be identified based on the shift in the electrooxidation potential of heterocyclic nitrogenous bases toward more negative (cathodic) or positive (anodic) values. Drug intercalation into DNA shifts the electrochemical oxidation potential to positive values, indicating thermodynamically unfavorable process that hinders oxidation of nitrogenous bases in DNA. The potential shift toward the negative values indicates electrostatic interactions, e.g., drug binding in the DNA minor groove, since this process does not interfere with the electrochemical oxidation of bases. The concentration-dependent decrease in the intensity of electrochemical oxidation of DNA bases allows to quantify the type of interaction and calculate the binding constants.

MPFFPSDC: A multi-pooling feature fusion model for predicting synergistic drug combinations.

Drug combination therapies are common practice in the treatment of cancer, but not all combinations result in synergy. As traditional screening approaches are restricted in their ability to uncover synergistic drug combinations, computer-aided medicine is becoming a increasingly prevalent in this field. In this work, a predictive model of potential interactions between drugs named MPFFPSDC is presented, which can maintain the symmetry of drug inputs and eliminate inconsistencies in predictive results caused by different drug inputting sequences or positions. The experimental results show that MPFFPSDC outperforms comparative models in major performance indicators and exhibits better generalization for independent data. Furthermore, the case study demonstrates that our model can capture molecular substructures that contribute to the synergistic effect of two drugs. These results indicate that MPFFPSDC not only offers strong predictive performance, but also has good model interpretability that may provide new insights for the study of drug interaction mechanisms and the development of new drugs.

First Approval of Pacritinib as a Selective Janus Associated Kinase-2 Inhibitor for the Treatment of Patients with Myelofibrosis.

In this short perspective, the chemical structure, physical properties, synthesis, mechanism of action, and pharmacokinetic profile of pacritinib are summarized. It is an orally bioavailable and isoform-selective JAK-2 inhibitor for treating patients with myelofibrosis.

Polypharmacy and Drug Interactions in Geriatric Patients with Type 2 Diabetes Mellitus at the Internal Medicine Inpatient Installation at RSUP Dr. M. Djamil Padang

One of the diseases commonly suffered by geriatric patients is diabetes mellitus, more than 95% of diabetics suffer from type 2 DM. Type 2 DM has a 2.28 times higher risk in the elderly and a greater risk of suffering from geriatric syndromes, one of them is polypharmacy which can increase the potential for drug interactions. The purpose of this study was to describe polypharmacy and drug interactions and to analyze the correlation between polypharmacy and drug interactions in geriatric patients with type 2 DM at the Internal Medicine Inpatient Installation at RSUP Dr. M. Djamil Padang in 2021. This type of research is non-experimental using a cross sectional method. Retrieval of data is retrospective originating from the patients medical records. A total of 39 samples included in the inclusion criteria showed that the incidence of drug interactions in patients prescribing polypharmacy was 79.49%, with the highest severity of drug interactions was moderate at 74.46%, and the most pattern of drug interaction mechanisms was pharmacodynamics at 78.72%. In this study it can be concluded that there is a strong and significant corelation between polypharmacy and the potential for drug interactions (p=0.000, r=0.570), which means that the more drugs used, the more potential drug-drug interactions.

Drug Interactions in Neurology and Psychiatry

Among drug-drug interactions, pharmacokinetic drug interactions are those in which multiple drugs interact to produce fluctuations in their blood concentrations, and mainly involve drug-metabolizing enzymes (cytochrome P450, UDP-glucuronyltransferase) and drug transporters (P-glycoprotein, etc.). The risk of drug interactions along with an increase in the number of drugs being used simultaneously; therefore, it is important to know the mechanisms of drug interactions, and the drugs to be wary of, as well as to make efforts to reduce the number of drugs used as much as possible.

IMSEA: A Novel Metabolite Set Enrichment Analysis Strategy to Decipher Drug Interactions.

Drug combinations are commonly used to treat various diseases to achieve synergistic therapeutic effects or to alleviate drug resistance. Nevertheless, some drug combinations might lead to adverse effects, and thus, it is crucial to explore the mechanisms of drug interactions before clinical treatment. Generally, drug interactions have been studied using nonclinical pharmacokinetics, toxicology, and pharmacology. Here, we propose a complementary strategy based on metabolomics, which we call interaction metabolite set enrichment analysis, or iMSEA, to decipher drug interactions. First, a digraph-based heterogeneous network model was constructed to model the biological metabolic network based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Second, treatment-specific influences on all detected metabolites were calculated and propagated across the whole network model. Third, pathway activity was defined and enriched to quantify the influence of each treatment on the predefined functional metabolite sets, i.e., metabolic pathways. Finally, drug interactions were identified by comparing the pathway activity enriched by the drug combination treatments and the single drug treatments. A data set consisting of hepatocellular carcinoma (HCC) cells that were treated with oxaliplatin (OXA) and/or vitamin C (VC) was used to illustrate the effectiveness of the iMSEA strategy for evaluation of drug interactions. Performance evaluation using synthetic noise data was also performed to evaluate sensitivities and parameter settings for the iMSEA strategy. The iMSEA strategy highlighted synergistic effects of combined OXA and VC treatments including the alterations in the glycerophospholipid metabolism pathway and glycine, serine, and threonine metabolism pathway. This work provides an alternative method to reveal the mechanisms of drug combinations from the viewpoint of metabolomics.

PPARα Induces the Expression of CAR That Works as a Negative Regulator of PPARα Functions in Mouse Livers.

The nuclear receptor peroxisome proliferator-activated receptor α (PPARα) is a transcription factor that controls the transcription of genes responsible for fatty acid metabolism. We have recently reported a possible drug-drug interaction mechanism via the interaction of PPARα with the xenobiotic nuclear receptor constitutive androstane receptor (CAR). Drug-activated CAR competes with the transcriptional coactivator against PPARα and prevents PPARα-mediated lipid metabolism. In this study, to elucidate the crosstalk between CAR and PPARα, we focused on the influence of PPARα activation on CAR's gene expression and activation. Male C57BL/6N mice (8-12 weeks old, n = 4) were treated with PPARα and CAR activators (fenofibrate and phenobarbital, respectively), and hepatic mRNA levels were determined using quantitative reverse transcription PCR. Reporter assays using the mouse Car promoter were performed in HepG2 cells to determine the PPARα-dependent induction of CAR. CAR KO mice were treated with fenofibrate, and the hepatic mRNA levels of PPARα target genes were determined. Treatment of mice with a PPARα activator increased Car mRNA levels as well as genes related to fatty acid metabolism. In reporter assays, PPARα induced the promoter activity of the Car gene. Mutation of the putative PPARα-binding motif prevented PPARα-dependent induction of reporter activity. In electrophoresis mobility shift assay, PPARα bound to the DR1 motif of the Car promoter. Since CAR has been reported to attenuate PPARα-dependent transcription, CAR was considered a negative feedback protein for PPARα activation. Treatment with fenofibrate induced the mRNA levels of PPARα target genes in Car-null mice more than those in wild-type mice, suggesting that CAR functions as a negative feedback factor for PPARα.

Novel food drug interaction mechanism involving acyclovir, chitosan and endogenous mucus

Drug absorption from drug products may be affected by pharmaceutical excipients and/or food additives through different mechanisms. Chitosan is a recognized nutraceutical, with potential as an excipient due to its permeability enhancer properties. While chitosan properties have been evaluated in in vitro and pre-clinical models, studies in humans are scarce. Unexpectedly, a controlled clinical trial showed chitosan actually reduced acyclovir bioavailability. The effect seems to be related to an interaction with gastrointestinal mucus that prevents further absorption, although more in depth research is needed to unravel the mechanism. In this paper, we propose a mechanism underlying this excipient effect. The mucus – chitosan interaction was characterized and its effect on acyclovir diffusion, permeation and bioaccessibility was investigated. Further, pharmacokinetic modeling was used to assess the clinical relevance of our findings. Results suggest that in situ coacervation between endogenous mucus and chitosan rapidly entrap 20–30% of acyclovir dissolved dose in the intestinal lumen. This local reduction of acyclovir concentration together with its short absorption window in the small intestine would explain the reduction in acyclovir Cmax and AUC. This study highlights the importance of considering mucus in any biorelevant absorption model attempting to anticipate the effect of chitosan on drug absorption.

A biophysical approach of cytarabine anticancer drug insights into human serum albumin and checkpoint kinase 1

The present studies used biophysical techniques to examine the binding interaction mechanism of cytarabine anticancer drugs with human serum albumin (HSA) and checkpoint kinase 1. The UV–vis absorption spectrum of the cytarabine-HSA complex reveals a blue shift due to the presence of the cytarabine drug. The results of the fluorescence spectroscopy indicate that static quenching happened as the cytarabine drug concentration in HSA was increased and thermodynamical parameters, binding constant (K) were calculated at different temperatures (293 K, 298 K, 303 K) results have good agreement with molecular docking studies. Molecular docking and molecular dynamics studies were carried out for both HSA and Chk1 protein complexes. In continuing with docking, we have also carried out DFT analysis at the cytarabine drug binding active site of HSA and Chk1 molecule to understand the internal stability at the atomic level.

Modern view on the age-associated gastrointestinal diseases. Review

The substantial improvement of diagnostic methods, treatment and preventive measures in recent years resulted in the significant increase in life expectancy, which in turn contributed to an increase in the frequency of chronic noncommunicable diseases among elderly patients. Pathological conditions that are related to the gastrointestinal (GI) tract are an extremely common reason for consultations among patients of all ages, but the elderly people are most prone to the development of GI diseases. Available information regarding which GI changes are normal in older age and which ones are pathologic is limited, and the available data is usually contradictory. The diagnostic algorithm in elderly patients with GI symptoms is even more complicated by the frequent presence of concomitant diseases. In addition, the elderlies usually have atypical manifestations of the GI disease with subtle symptoms; therefore, doctors who are not familiar with It may not diagnose the disease timely. Drug side effects manifested in the GI tract are also a common phenomenon in elderly patients and they can also change the clinical picture and complicate the diagnosis of GI pathologies. Thus, elderly patients represent a population group among whom effective detection and correct diagnosis of GI diseases become extremely difficult for physicians who are not familiar with the features of age‑related changes in the GI tract and peculiarities of GI diseases. Therefore, the expansion of knowledge about the course of GI disorders in this category of patients is absolutely necessary for further improvement of the quality and duration of life of such patients. Our review presents modern data on the prevalence of gastrointestinal tract pathologies, their role in the general morbidity of the population, the most typical disorders of the gastrointestinal tract in elderly patients, the mechanism of drug interactions and side effects of drugs that can cause the development of complications from the GI tract.&#x0D;

Solvent Free Twin Screw Processed Silybin Nanophytophospholipid: In Silico, In Vitro and In Vivo Insights.

Silybin (SIL) is a polyphenolic phytoconstituent that is commonly used to treat liver disorders. It is difficult to fabricate an orally delivered SIL product due to its low oral bioavailability (0.95%). Therefore, the current research focusses on the development of a novel composition of a phospholipid complex, termed as nanophytophospholipid, of SIL by employing a unique, solvent-free Twin Screw Process (TSP), with the goal of augmenting the solubility and bioavailability of SIL. The optimised SIL-nanophytophospholipid (H6-SNP) was subjected to physicochemical interactions by spectrometry, thermal, X-ray and electron microscopy. The mechanism of drug and phospholipid interaction was confirmed by molecular docking and dynamics studies. Saturation solubility, in vitro dissolution, ex vivo permeation and preclinical pharmacokinetic studies were also conducted. H6-SNP showed good complexation efficiency, with a high practical yield (80%). The low particle size (334.7 ± 3.0 nm) and positively charged zeta potential (30.21 ± 0.3 mV) indicated the immediate dispersive nature of H6-SNP into nanometric dimensions, with good physical stability. Further high solubility and high drug release from the H6-SNP was also observed. The superiority of the H6-SNP was demonstrated in the ex vivo and preclinical pharmacokinetic studies, displaying enhanced apparent permeability (2.45-fold) and enhanced bioavailability (1.28-fold). Overall, these findings indicate that not only can phospholipid complexes be formed using solvent-free TSP, but also that nanophytophospholipids can be formed by using a specific quantity of lipid, drug, surfactant, superdisintegrant and diluent. This amalgamation of technology and unique composition can improve the oral bioavailability of poorly soluble and permeable phytoconstituents or drugs.

Enalapril increases the urinary excretion of metformin in rats by inducing multidrug and toxin excretion protein 1 in the kidney.

Two-thirds of patients with type 2 diabetes mellitus (T2DM) have hypertension, and thus the combination of two or more drugs to treat these diseases is common. It has been shown that the combination of metformin and enalapril has beneficial effects, but few studies have evaluated the interactions between these two drugs. In this study we investigated the effects of enalapril on the pharmacokinetics and urinary excretion of metformin in rats, with a focus on transporter-mediated drug interactions. Rats were orally dosed with metformin alone (100 mg/kg) or in combination with enalapril (4 mg/kg). The concentration of metformin was measured by HPLC and the level of organic cation transporters (rOCTs) and multidrug and toxin excretion protein 1 (rMATE1), which mediate the uptake and efflux of metformin, respectively, were evaluated by immunoblotting. After single and 7-day dosing, the plasma concentration of metformin in the co-administration group was significantly lower than that in the metformin-only group, and the CL/F and urinary excretion were increased in the co-administration group. Enalapril did not affect the Kp of metformin but elevated slice-uptake of metformin. The expression of rMATE1 was increased, whereas rOCT2 expression was decreased in rat kidney. Importantly, long-term co-administration of metformin and enalapril markedly decreased the level of lactic acid and uric acid in the blood. Enalapril increases the urinary excretion of metformin through the up-regulation of rMATE1. This reveals a new mechanism of drug interactions and provides a basis for drug dosage adjustment when these drugs are co-administered. This article is protected by copyright. All rights reserved.