Drug-Drug Interactions in Patients with Breast Cancer

The research paper investigates the intricate landscape of drug-drug interactions (DDIs) within the context of breast cancer treatment, with a particular focus on the elderly population and the use of complementary and alternative medicine (CAM). The study underscores the heightened susceptibility of elderly patients to DDIs due to the prevalence of polypharmacy and the widespread utilization of CAM among breast cancer patients. The potential ramifications of DDIs, encompassing adverse drug events and diminished treatment efficacy, are elucidated. The paper accentuates the imperative for healthcare providers to comprehensively understand both conventional and CAM therapies, enabling them to provide patients with informed guidance regarding safe and efficacious treatment options, culminating in enhanced patient outcomes.

P-glycoprotein mediated interactions between Chinese materia medica and pharmaceutical drugs

P-glycoprotein(P-gp)is an important transmembrane ATP-binding cassette(ABC)drug efflux transporter expressed in various human tissues such as the intestines,liver,kidneys,and bloodbrain barrier.It limits the intracellular concentration of xenobiotics by pumping them out of the cells,affecting drug pharmacokinetics and therapeutic effects.With its broad substrate specificity,it has the potential to remove a wide range of drugs from Chinese materia medica(CMM),including conventional medicines and active compounds.Increasing evidence has confirmed the superior therapeutic effectiveness of CMM in treating a wide range of diseases worldwide,as well as in conjunction with western drugs.As a result,herbal medicine-drug compounds have prompted widespread concern,with the majority of these interactions involving transporters such as P-gp.This review systematically summarizes the inhibition or induction of P-gp expression/function by active CMM compounds and the underlying regulatory mechanisms.It will aid in improving understanding of the synergistic or inhibiting effects associated with transporter P-gp as well as rational safety concerns for using CMM,particularly in combination with drugs.

<i>In Vitro</i>and <i>in Vivo</i>(Mouse) Evaluation of Drug-Drug Interactions of Repaglinide with Anti-HIV Drugs

Repaglinide is type 2 short acting anti-diabetic drug which is primarily metabolized by CYP2C8 and CYP3A4 and is also a substrate of influx transporter OATP1B1. HIV drugs are potent inhibitors of CYP3A4 and OATP transporters. Several drug-drug interactions (DDIs) were noticed when protease inhibitors (PIs) coadministered with drugs metabolized by CYP3A4. The PIs are also potent mechanism based inhibitors, out which ritonavir is most potent. In the current study we evaluated in vitro (mouse and human liver microsomes) and in vivo DDIs of repaglinide with anti-HIV drugs. Out of the following tested drugs (Amprenavir, Indinavir, Nelfinavir, Ritonavir, Saquinavir, Delavirdine, Maraviroc, Efavirenz, Nevirapine and Ketoconazole) Amprenavir (APV), Ritonavir (RTV) and Ketoconazole (KTZ) showed inhibition of OH-repaglinide formation in human and mouse liver microsomes. The positive reversible inhibitions were further tested for irreversible inhibitions where we didn’t observe any irreversible inhibitions. In vitro inhibitions were further evaluated in the in vivo pharmacokinetics (mouse) where repaglinide pharmacokinetics was altered by RTV and KTZ. The DDIs in both studies were very strong;the dose of repaglinide is reduced to 20 fold. In conclusion, there could be possible DDIs when RTV dosed with repaglinide;we have also demonstrated that mouse could be useful preclinical tool when used in conjunction with in vitro screening models for DDIs.

Three-dimensional aspects of formulation excipients in drug discovery:a critical assessment on orphan excipients,matrix effects and drug interactions

Formulation/pharmaceutical excipients play a major role in formulating drug candidates,with the objectives of ease of administration,targeted delivery and complete availability.Many excipients used in pharmaceutical formulations are orphanized in preclinical drug discovery.These orphan excipients could enhance formulatability of highly lipophilic compounds.Additionally,they are safe in preclinical species when used below the LD50 values.However,when the excipients are used in formulating compounds with diverse physico-chemical properties,they pose challenges by modulating study results through their bioanalytical matrix effects.Excipients invariably present in study samples and not in the calibration curve standards cause over-/under-estimation of exposures.Thus,the mechanism by which excipients cause matrix effects and strategies to nullify these effects needs to be revisited.Furthermore,formulation excipients cause drug interactions by moderating the pathways of drug metabolizing enzymes and drug transport proteins.Although it is not possible to get rid of excipient driven interactions,it is always advised to be aware of these interactions and apply the knowledge to draw meaningful conclusions from study results.In this review,we will comprehensively discuss a)orphan excipients that have wider applications in preclinical formulations,b)bioanalytical matrix effects and possible approaches to mitigating these effects,and c)excipient driven drug interactions and strategies to alleviate the impacts of drug interactions.

Drug interactions of dipeptidyl peptidase 4 inhibitors involving CYP enzymes and P-gp efflux pump

Dipeptidyl peptidase 4(DPP4) inhibitors are oral antidiabetic drugs approved to manage type 2 diabetes mellitus. Saxagliptin is a substrate of CYP3A4/5 enzymes while other DPP4 inhibitors such as sitagliptin, linagliptin, gemigliptin and teneligliptin are weak substrates of CYP3A4. DPP4 inhibitors have also been identified as substrates of P-gp. Hence, the drugs inhibiting or inducing CYP3A4/5 enzymes and/or P-gp can alter the pharmacokinetics of DPP4 inhibitors. This review is aimed to identify the drugs interacting with DPP4 inhibitors. The plasma concentrations of saxagliptin have been reported to be increased significantly by the concomitant administration of ketoconazole or diltiazem while no significant interactions between various DPP4 inhibitors and drugs like warfarin, digoxin or cyclosporine have been identified.

Major bleeding events in octagenarians associated with drug interactions between dabigatran and P-gp inhibitors

Background The direct oral anticoagulant dabigatran does not require any routine therapeutic drug monitoring.Yet,concerns about possible drug interactions susceptible to increase its inherent bleeding risk,especially in very elderly patients,have been raised recently.The aim of our study was to evaluate to what extent the co-prescription of P-gp inhibitors with dabigatran may increase its plasma levels and lead to bleeding complications,in usual conditions of care of the very elderly.Methods Fifty-eight patients over 85 years old with non valvular atrial fibrillation receiving dabigatran were included in a prospective cohort.Prescriptions were screened for the presence of P-gp inhibitors(Group A)or not(Group B).Results Patients from Group A had increased dabigatran mean plasma concentrations as compared with patients from Group B(A vs.B:182.2±147.3 vs.93.7±64.9 ng/m L).One third of the patients from Group A had dabigatran concentrations that were deemed"out of range"versus none in Group B(P=0.05).This was associated with more frequent bleeding complications in Group A(A:30.4%,B:8.6%,P=0.04).Conclusion In our cohort of very elderly patients,at least,the co-prescription of dabigatran with P-gp inhibitors in usual conditions of care resulted in higher dabigatran plasma concentrations and more frequent bleeding occurrences.

Prevalence of Potential Drug-Drug Interactions in Hospitalized Surgical Patients

The objective of this study is to estimate the prevalence and describe the characteristics of pDDIs （potential drug-drug interactions） in medical prescriptions of hospitalized surgical patients. In this cross-sectional study, we analyzed 370 medical prescriptions from the surgery unit of a Mexican public teaching hospital. The identification and classification of potential drug-drug interactions were performed with the Micromedex 2.0 electronic drug information database. Results were analyzed with descriptive statistics and we estimated OR （odds ratio） to determine associated risk factors. From the study, it was found that the prevalence of potential drug-drug interactions was 45.9%. A total of 385 interactions were identified. Of these, 54.3% were classified as major and 60.5% as pharmacodynamic. Prescriptions for more than seven drugs （OR =7.33, CI （confidence interval） = 4.59-11.71） and advanced age 〉 60 years, （OR = 1.79, CI = 1.06-2.74） were positively associated with the presence of potential drug-drug interactions. We found a high prevalence of clinically relevant pDDIs in the surgery unit. In view of this outcome, the safety of drug combinations in hospitalized surgical patients should be evaluated during the prescription process in order to prevent adverse events.

Rational prescription of drugs within similar therapeutic or structural class for gastrointestinal disease treatment: Drug metabolism and its related interactions

AIM:To review and summarize drug metabolism and its related interactions in prescribing drugs within the similar therapeutic or structural class for gastrointestinal disease treatment so as to promote rational use of medicines in clinical practice.METHODS:Relevant literature was identified by performing MEDLINE/Pubmed searches covering the period from 1988 to 2006.RESULTS:Seven classes of drugs were chosen,including gastric proton pump inhibitors,histamine H2-receptor antagonists,benzamide-type gastroprokinetic agents,selective 5-HT3 receptor antagonists,fluoroquinolones,macrolide antibiotics and azole antifungals.They showed significant differences in metabolic profile(i.e.,the fraction of drug metabolized by cytochrome P450(CYP),CYP reaction phenotype,impact of CYP genotype on interindividual pharmacokinetics variability and CYP-mediated drug-drug interaction potential).Many events of severe adverse drug reactions and treatment failures were closely related to the ignorance of the above issues.CONCLUSION:Clinicians should acquaint themselves with what kind of drug has less interpatient variability in clearance and whether to perform CYP genotyping prior to initiation of therapy.The relevant CYP knowledgehelps clinicians to enhance the management of patients with gastrointestinal disease who may require treatment with polytherapeutic regimens.

Possibility of Drug-Drug Interaction in Prescription Dispensed by Community and Hospital Pharmacy

Objective: To analyze the use of all subsidized prescription drugs including their use of drug combination generally accepted as carrying a risk of severe interactions. Methodology: In a cross sectional study, we analyzed all prescriptions (n = 1014) involving two or more drugs dispensed to the population (age range 4-85 years) from all pharmacies, clinics and hospitals. Data were stratified by age and sex, and frequency of common interacting drugs. Potential drug interactions were classified according to clinical relevance as significance of severity (types A: major, B: moderate, and C: minor) and documented evidence (types 1, 2, 3, and 4). Result and Discussion: The growing use of pharmacological agents means that drug interactions are of increasing interest for public health. Monitoring of potential drug interactions may improve the quality of drug prescribing and dispensing, and it might form a basis for education focused on appropriate prescribing. To make the manifestation of adverse interaction subside, management strategies must be exercised if two interacting drugs have to be taken with each other, involving: adjusting the dose of the object drug;spacing dosing times to avoid the interaction. The pharmacist, along with the prescriber has a duty to ensure that patients are aware of the risk of side effects and a suitable course of action they should take. Conclusion: It is unrealistic to expect clinicians to memorize the thousands of drug-drug interactions and their clinical significance, especially considering the rate of introduction of novel drugs and the escalating appreciation of the importance of pharmacogenomics. Reliable regularly updated decision support systems and information technology are necessary to help avert dangerous drug combinations.

Overview of the detection methods for equilibrium dissociation constant KD of drug-receptor interaction

Drug-receptor interaction plays an important role in a series of biological effects, such as cell pro- liferation, immune response, tumor metastasis, and drug delivery. Therefore, the research on drug-re- ceptor interaction is growing rapidly. The equilibrium dissociation constant （KD） is the basic parameter to evaluate the binding property of the drug-receptor. Thus, a variety of analytical methods have been established to determine the KD values, including radioligand binding assay, surface plasmon resonance method, fluorescence energy resonance transfer method, affinity chromatography, and isothermal ti- tration calorimetry. With the invention and innovation of new technology and analysis method, there is a deep exploration and comprehension about drug-receptor interaction. This review discusses the differ- ent methods of determining the KD values, and analyzes the applicability and the characteristic of each analytical method. Conclusively, the aim is to provide the guidance for researchers to utilize the most appropriate analytical tool to determine the KD values.

Evaluation of the Mrp2-mediated flavonoid-drug interaction potential of quercetin in rats and in vitro models

Quercetin is a biologically active flavonoid that has been used as a popular health supplement.It is reported that quercetin may cause flavonoid-drug interaction mediated by P-glycoprotein,the most predominant efflux transporter.In this study,we comprehensively evaluated the potential of the pharmacokinetic interaction of quercetin mediated by multidrug resistance-associated protein 2(MRP2),another major efflux transporter.MRP2-transfected MDCKII cells and LS174T cells were used to evaluate the potential inhibition and induction of MRP2 by quercetin in vitro.To evaluate the induction effect of quercetin on Mrp2 in vivo,Mrp2 mRNA expression in rat liver,kidney,and small intestinal tissues was determined after the oral administration of quercetin(50,100,or 250 mg/kg)for seven days.Mrp2-mediated interaction potential was also evaluated by the pharmacokinetic study of phenolsulfonphthalein in rats after single or multiple doses of quercetin.Additionally,the effect of quercetin on absorption of docetaxel,a P-glycoprotein and CYP3A4 substrate,was also evaluated.Quercetin inhibited the function of MRP2 at 10μM and induced the mRNA expression of MRP2 at 50μM in vitro.Additionally,at 100 mg/kg,quercetin markedly increased Mrp2 expression in the small intestine of rats.However,there was no significant change in phenolsulfonphthalein pharmacokinetics due to single-(50,100,or 250 mg/kg)or multiple-dose(50,100,or 250 mg/kg for seven days)quercetin co-administration.By contrast,a significant interaction caused by quercetin(100 mg/kg)was observed in the absorption of docetaxel.The results suggested that although quercetin modulates the function and expression of MRP2 in vitro,it may have a low potential of Mrp2-mediated interaction and present negligible safety concerns related to the interaction.

Potential drug–drug interactions in pediatric wards of Gondar University Hospital,Ethiopia:A cross sectional study

Objective: To determine the prevalence, level of severity of potential drug–drug interactions(PDDIs) and the associated factors for PDDIs in hospitalized pediatric patients of Gondar University Hospital.Methods: A retrospective cross-sectional study was conducted for a period of 3 months from March to May 2014 in pediatric wards of Gondar University Hospital. Systematic random sampling technique was used to select charts from all pediatric patients' charts with every 7th interval to get sample size of 384. Univariate and multivariate analysis were performed to compute crude odds ratio and adjusted odds ratio respectively. Statistical significance was set at P value < 0.05.Results: A total of 176(45.8%) patients had at least one PDDI. A total of 393 PDDIs,which were comprised of 283 types of interacting combinations, were identified. Of the total of 393 PDDIs, most were of moderate severity [201(51%)] followed by minor [152(39%)] and major severity [40(10%)]. The most common interacting pairs of major severity were gentamicin + furosemide(6), cotrimoxazole + methotrexate(4) and phenytoin + artemether(4). The occurrence of PDDIs was significantly associated with age and polypharmacy.Conclusions: The study showed that most of the interactions had moderate severity followed by minor severity. Age and polypharmacy were found to show statistically significant association with the occurrence of PDDIs. Due to sensitive nature of pediatrics population, close monitoring is recommended for the detection and management of PDDIs to prevent its negative consequences.

An Updated Mini Review on Grapefruit: Interactions with Drugs, Obesity and Cardiovascular Risk Factors

The paper examines the effects of grapefruit consumption in relation to drugs, obesity and cardiovascular risk factors. The review includes the most updated studies found in Pub-Med. The grapefruit effect refers to the ability of grapefruit juice and supplements to interact with a wide variety of pharmaceuticals, either enhancing or limiting their systemic availability. Due to altering the active dosage of the pharmaceutical, Grapefruit juice is commonly not allowed to be used alongside with many drugs. Naringin is the most important one, which can inhibit absorption of some drugs but more commonly 6’7’-dihydroxybergamottin, which inhibits CYP3A4. Lately, grapefruit has been found both in rats and adults to reduce body weight, blood pressure, improve lipid and hepatic profile and decrease platelet aggregation. These promising results must be followed by additional studies in order to add to the importance of the role and effects of grapefruit as part of our diet.

Tobacco smoking and its drug interactions with comedications involving CYP and UGT enzymes and nicotine

Tobacco smoking is a global public health threat causing several illnesses including cardiovascular disease(Myocardial infarction), cerebrovascular disease(Stroke), peripheral vascular disease(Claudication), chronic obstructive pulmonary disease, asthma, reduced female infertility, sexual dysfunction in men, different types of cancer and many other diseases. It has been estimated in 2015 that approximately 1.3 billion people smoke, around the globe. Use of medications among smokers is more common, nowadays. This review is aimed to identify the medications affected by smoking, involving Cytochrome P450(CYP)and uridine diphosphate-glucuronosyltransferases(UGTs) enzymes and Nicotine. Polycyclic aromatic hydrocarbons(PAHs) of tobacco smoke have been associated with the induction of CYP enzymes such as CYP1A1, CYP1A2 and possibly CYP2E1 and UGT enzymes. The drugs metabolized by CYP1A1,CYP1A2, CYP2E1 and UGT enzymes might be affected by tobacco smoking and the smokers taking medications metabolized by those enzymes, may need higher doses due to decreased plasma concentrations through enhanced induction by PAHs of tobacco smoke. The prescribers and the pharmacists are required to be aware of medications affected by tobacco smoking to prevent the toxicityassociated complications during smoking cessation.

Molecular interactions between anticancer drugs and iodinated contrast media: An in vitro spectroscopic study

Purpose: The purpose of this study is to assess molecular interactions between several anticancer drugs and an iodinated contrast medium by Fourier transform infrared spectroscopy (FT-IR) and ultraviolet-visible spectroscopy (UV-Vis). Materials and Methods: Iopamidol (IPM) was used as an iodinated contrast medium, and mitomycin C (MTI), epirubicin hydrochloride (EPI), cisplatin (CDDP), 5-fluorouracil (5FU), irinotecan hydrochloride (CPT11), gemcitabine hydrochloride (dFdC), carboplatin (CBDCA), oxaliplatin (1OHP), paclitaxel hydrochloride (TAX) and docetaxel trihydrate (TXT) were used as anticancer drugs. For FT-IR, the purified IPM was mixed stoichiometrically with each anticancer drug as well as with a combination of MTI and EPI. After measuring each separated sample and the mixtures, the spectra of the mixtures were compared with the spectra of the sum of pure samples or the combination. For UV-Vis, IPM and anticancer drugs were dissolved in pure water;subsequently for the titration experiments, the mixtures were prepared by varying the molar ratio. IR absorption corresponds to stretching vibrations between atoms having covalent bonding, whereas UV-Vis spectra depend on molecular dynamics and shapes. Both UV-Vis and IR spectra change when there are molecular interactions such as aromatic ring stacking and hydrogen bonding. Result: IPM exhibited molecular interactions with MTI, EPI, CDDP, dFdC, CBDCA, 1OHP, TAX and TXT, as well as with the combination of MTI and EPI on FT-IR. However, molecular interactions were not observed on UV-Vis. Conclusion: Several anticancer drugs have molecular interactions with IPM, which could be clinically utilized for superselective intraarterial infusion chemotherapy.

Fluid-Structure Interaction Analysis for Drug Transport in a Curved Stenotic Right Coronary Artery

A blockage of blood vessels resulting from thrombus or plaque deposit causes serious cardiovascular diseases. This study developed a computational model of blood flow and drug transport to investigate the effectiveness of drug delivery to the stenotic sites. A three-dimensional (3D) model of the curved stenotic right coronary artery (RCA) was reconstructed based on the clinical angiogram image. Then, blood flow and drug transport with the flexible RCA wall were simulated using the fluid structure interaction (FSI) analysis and compared with the rigid RCA wall. Results showed that the maximal total displacement and von Mises stress of the flexible RCA model are 2.14 mm and 92.06 kPa. In addition, the effective injecting time point for the best performance of drug delivery was found to be between 0 s and 0.15 s (i.e., the fluid acceleration region) for both rigid and flexible RCA models. However, there was no notable difference in the ratio of particle deposition to the stenotic areas between the rigid and flexible RCA models. This study will be significantly useful to the design of a drug delivery system for the treatment of the stenotic arteries by targeting drugs selectively to the stenotic sites.

Impact of Drug-Drug Interaction between CDK4/6 Inhibitors and Proton Pump Inhibitors on Survival Outcomes in the Treatment of Metastatic Breast Cancer—Real World Data from a Portuguese Center

Introduction: Proton pump inhibitors (PPi) are widely prescribed, including in patients undergoing treatment for advanced breast cancer (ABC). Due to the pharmacokinetic characteristics of the CDK4/6 inhibitor (Ci) palbociclib a drug interaction with PPi was hypothesized. It was shown in a retrospective study that this association was an independent predictive factor for worse progression-free survival (PFS). Objective: To verify the impact of concomitant administration of PPi with Ci on overall survival (OS) and PFS. Material and Methods: This is a retrospective cohort study of patients treated with Ci for HR+HER2-ABC in the period from Feb/2017 to Aug/2020. SPSS software was used for data processing. Univariate analysis was done by the Kaplan-Meier method and log-rank test, and multivariate analysis by COX regression. P-value < 0.05 was considered significant. Results: 80 patients were included. The median age at diagnosis of ABC was 56 years (25 - 75). Treatment with Ci was 1st line for ABC in 68.8%. Choice of Ci was palbociclib in 73.8% (n = 59) and ribociclib in 26.3% (n = 21). The hormone partner was a nonsteroidal aromatase inhibitor in 45.0%, and fulvestrant in 55.0% of cases. 37.5% of patients were on PPi, and 70.0% of them were during the entire treatment (23.3% omeprazole, 73.4% pantoprazole, 3.3% others). Patients taking concomitant PPi and Ci had lower OS (OS-3 years 42.6% vs. 63.4%, p = 0.254) and PFS (PFS med 15 m. vs. 21 m., p = 0.733), although with no statistically significant difference. Discussion: In the sample, there was a numerical difference, without the statistical significance in the use of PPi in the survival of patients under Ci. This difference could be more evident with a longer follow-up and a larger sample size. This study intends to alert to the growing importance of checking for drug interactions. Polymedication, advanced age and the presence of several comorbidities are real problems in patients with ABC. Conclusion: Real-world data from this center demonstrate a negative, non-statistically significant impact of PPi treatment on survival outcomes, in patients treated with Ci for HR+HER2-ABC.

Short-Term Drug-Drug Interaction between Sildenafil and Bosentan under Long-Term Use in Patients with Pulmonary Arterial Hypertension

Sildenafil and bosentan are often co-administered for pulmonary arterial hypertension (PAH) treatment. The plasma concentration of sildenafil can be decreased by half if co-administered with bosentan. Many patients take these agents simultaneously in the morning and the evening. The aim of this study was to examine the pharmacokinetics of sildenafil which was interfered with bosentan administration to ascertain whether these agents should be given concomitantly or separately. A two-way crossover study was conducted in 6 PAH patients with combination therapy of sildenafil and bosentan. Participants underwent the sequence of treatment phases: phase S (sildenafil administered 3 h before bosen-tan);phase B (bosentan administered 3 h before sildenafil);and phase C (administered concomitantly). Blood samples were collected on the last day of each phase. There was no significant difference in maximum plasma concentration or area under the plasma concentration-time curve (AUC0-8) between phase C and phase S (95.5 ± 24.8 vs. 72.9 ± 40.9 (p = 0.07), 209.7 ± 81.8 vs. 180.2 ± 126.4 (p = 0.24), respectively) or between phases C and B (87.8 ± 42.0 vs. 99.6 ± 33.9 (p = 0.59), 197.2 ± 88.2 vs. 240.7 ± 121.8 (p = 0.19), respectively) (ng/mL, mean ± standard deviation). Large intra-and inter-individual variability in sildenafil concentration was noted. The timing of administration of sildenafil and bosentan does not significantly influence the plasma concentration of sildenafil. Physicians do not need to be overly concerned about the timing of administration of these drugs to maximize the sildenafil concentration.

Potential Mechanism of Herb-Drug Interaction Mediated by Angelica dahurica: Inhibition on CYP3A Enzymes in Rats

Angelica dahurica is commonly referred to as ‘Baizhi’ in China and has been noted for its therapeutic significance. The major active ingredients of Angelica dahurica is coumarin, which is reported as a kind of potent inhibitor of cytochrome P450 enzymes (CYP450s). The aim of this study was to investigate the inhibition of CYP3A enzymes by total coumarin extract (TCE) obtained from dried root of Angelica dahurica by using in situ single pass intestinal perfusion (SPIP) and in situ liver perfusion in rats. When midazolam (MDZ) which is a substrate of CYP3A co-perfused with TCE (198 μg/mL) from Baizhi in duodenum and ileum segments, the Peff of MDZ has increased significantly compared with the MDZ single perfused group (p 0.05) (n = 6). During in situ liver perfusion study, the results demonstrated that, 3 days oral administration of TCE obtained from Baizhi could significantly reduce the elimination rate of MDZ in the perfusate (p Angelica dahurica extract co-administrated with drugs which are the substrates of CYP3A, much more attention should be paid rather than that of other CYP450 enzymes. These findings may facilitate in predicting possible herb-drug interactions (HDIs) when Angelica dahurica is used in combination with other drugs, and decrease the incidence of the CYP450-mediated HDIs.

Role of non-steroidal anti-inflammatory drugs on intestinal permeability and nonalcoholic fatty liver disease

The use of non-steroidal anti-inflammatory drugs(NSAIDs) is widespread worldwide thanks to their analgesic, anti-inflammatory and antipyretic effects. However, even more attention is placed upon the recurrence of digestive system complications in the course of their use. Recent data suggests that the complications of the lower gastro-intestinal tract may be as frequent and severe as those of the upper tract. NSAIDs enteropathy is due to enterohepatic recycling of the drugs resulting in a prolonged and repeated exposure of the intestinal mucosa to the compound and its metabolites. Thus leading to so-called topical effects, which, in turn, lead to an impairment of the intestinal barrier. This process determines bacterial translocation and toxic substances of intestinal origin in the portal circulation, leading to an endotoxaemia. This condition could determine a liver inflammatory response and might promote the development of nonalcoholic steatohepatitis, mostly in patients with risk factors such as obesity, metabolic syndrome and a high fat diet, which may induce a small intestinal bacterial overgrowth and dysbiosis. This alteration of gut microbiota may contribute to nonalcoholic fatty liver disease and its related disorders in two ways: firstly causing a malfunction of the tight junctions that play a critical role in the increase of intestinal permeability, and then secondly leading to the development of insulin resistance, body weight gain, lipogenesis, fibrogenesis and hepatic oxidative stress.