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Blood–brain barrier (BBB) strictly controls matter exchange between blood and brain, and severely limits brain penetration of systemically administered drugs, resulting in ineffective drug therapy of brain diseases. However, during the onset and progression of brain diseases, BBB alterations evolve inevitably. In this review, we focus on nanoscale brain-targeting drug delivery strategies designed based on BBB evolutions and related applications in various brain diseases including Alzheimer's disease, Parkinson's disease, epilepsy, stroke, traumatic brain injury and brain tumor. The advances on optimization of small molecules for BBB crossing and non-systemic administration routes (e.g., intranasal treatment) for BBB bypassing are not included in this review., Graphical abstract Blood–brain barrier (BBB) is evolving during the onset and progression of brain diseases. BBB evolution-based nanoscale brain-targeting drug delivery strategies are summarized in this review for various brain diseases.Image 1

Due to its safety, convenience, low cost and good compliance, oral administration attracts lots of attention. However, the efficacy of many oral drugs is limited to their unsatisfactory bioavailability in the gastrointestinal tract. One of the critical and most overlooked factors is the symbiotic gut microbiota that can modulate the bioavailability of oral drugs by participating in the biotransformation of oral drugs, influencing the drug transport process and altering some gastrointestinal properties. In this review, we summarized the existing research investigating the possible relationship between the gut microbiota and the bioavailability of oral drugs, which may provide great ideas and useful instructions for the design of novel drug delivery systems or the achievement of personalized medicine., Graphical abstract The gut microbiota may influence the bioavailability of oral drugs by the microbial enzyme activity, affecting the drug transport or changing the gastrointestinal properties. This may provide us some advice on preventing the possible drug–drug interaction and offer us some useful strategies for the drug delivery system design.Image 1

Small intestine in vitro models play a crucial role in drug transport research. Although conventional 2D cell culture models, such as Caco-2 monolayer, possess many advantages, they should be interpreted with caution because they have relatively poor physiologically reproducible phenotypes and functions. With the development of 3D culture technology, pluripotent stem cells (PSCs) and adult somatic stem cells (ASCs) show remarkable self-organization characteristics, which leads to the development of intestinal organoids. Based on previous studies, this paper reviews the application of intestinal 3D organoids in drug transport mediated by P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance protein 2 (MRP2). The advantages and limitations of this model are also discussed. Although there are still many challenges, intestinal 3D organoid model has the potential to be an excellent tool for drug transport research., Graphical abstract Intestinal 3D organoids are used to study the expression and function of ATP-binding-cassette transporters. Intestinal organoid model is becoming as a powerful tool for drug transport evaluation.Image 1

Urea transporters (UT) play a vital role in the mechanism of urine concentration and are recognized as novel targets for the development of salt-sparing diuretics. Thus, UT inhibitors are promising for development as novel diuretics. In the present study, a novel UT inhibitor with a diarylamide scaffold was discovered by high-throughput screening. Optimization of the inhibitor led to the identification of a promising preclinical candidate, N-[4-(acetylamino)phenyl]-5-nitrofuran-2-carboxamide (1H), with excellent in vitro UT inhibitory activity at the submicromolar level. The half maximal inhibitory concentrations of 1H against UT-B in mouse, rat, and human erythrocyte were 1.60, 0.64, and 0.13 μmol/L, respectively. Further investigation suggested that 8 μmol/L 1H more powerfully inhibited UT-A1 at a rate of 86.8% than UT-B at a rate of 73.9% in MDCK cell models. Most interestingly, we found for the first time that oral administration of 1H at a dose of 100 mg/kg showed superior diuretic effect in vivo without causing electrolyte imbalance in rats. Additionally, 1H did not exhibit apparent toxicity in vivo and in vitro, and possessed favorable pharmacokinetic characteristics. 1H shows promise as a novel diuretic to treat hyponatremia accompanied with volume expansion and may cause few side effects., Graphical abstract In the present study, a novel urea transporters (UT) inhibitor with a diarylamide scaffold was discovered by high throughput screening. Optimization of the hit compound E04 led to the identification of 1H, with orally diuretic activity, more powerful inhibition activity on UT-A1, favorable pharmacokinetic characteristics and without electrolyte disturbance.Image 1

Monoacylglycerol lipase (MAGL) is a serine hydrolase that plays a crucial role catalysing the hydrolysis of monoglycerides into glycerol and fatty acids. It links the endocannabinoid and eicosanoid systems together by degradation of the abundant endocannabinoid 2-arachidaoylglycerol into arachidonic acid, the precursor of prostaglandins and other inflammatory mediators. MAGL inhibitors have been considered as important agents in many therapeutic fields, including anti-nociceptive, anxiolytic, anti-inflammatory, and even anti-cancer. Currently, ABX-1431, a first-in-class inhibitor of MAGL, is entering clinical phase 2 studies for neurological disorders and other diseases. This review summarizes the diverse (patho)physiological roles of MAGL and will provide an overview on the development of MAGL inhibitors. Although a large number of MAGL inhibitors have been reported, novel inhibitors are still required, particularly reversible ones., Graphical abstract Monoacylglycerol lipase (MAGL) plays a crucial role catalysing the hydrolysis of monoglycerides. MAGL inhibitors have been considered as important agents in many therapeutic fields, including anti-nociceptive, anti-inflammatory and anti-cancer. The diverse (patho)physiological roles of MAGL and a comprehensive overview of reported MAGL inhibitors were summarized in this review.Image 1

Graphical abstract, Highlights • E. uchi stem bark hydroethanolic extract in zebrafish. • Evaluating the in silico pharmacokinetic and toxicological parameters. • Behavioral, biochemical and histopathological changes was dose dependent. • In silico bergenin and its metabolites showed high intestinal absorption. • Bergenin inhibited CYP2C9, CYP3A4 and CYP2C19., Endopleura uchi, is used for the treatment of inflammatory disease and related to the female reproductive tract. The aim of this study was to evaluate the acute toxicity of the Endopleura uchi stem bark hydroethanolic extract (EEu) in zebrafish, emphasizing the histopathological and biochemical parameters, as well as evaluating the in silico pharmacokinetic and toxicological parameters of the phytochemical/pharmacological marker, bergenin, as their metabolites. The animals were orally treated with EEu at a single dose of 75 mg/kg, 500 mg/kg, 1000 mg/kg and 3000 mg/kg. the oral LD50 of the EEu higher to the dose of 3000 mg/kg. Behavioral, biochemical and histopathological changes were dose dependent. In silico pharmacokinetic predictions for bergenin and its metabolites showed moderate absorption in high human intestinal absorption (HIA) and Caco-2 models, reduced plasma protein binding, by low brain tissue binding and no P-glycoprotein (P-Gp) inhibition. Their metabolism is defined by the CYP450 enzyme, in addition to bergenin inhibition of CYP2C9, CYP3A4 and CYP2C19. In the bergenin and its metabolites in silico toxicity test it have been shown to cause carcinogenicity and a greater involvement of the bergenin with the CYP enzymes in the I and II hepatic and renal metabolism’s phases was observed. It is possible to suggest that the histopathological damages are involved with the interaction of this major compound and its metabolites at the level of the cellular-biochemical mechanisms which involve the absorption, metabolization and excretion of these possible prodrug and drug.

Sepsis is an infection-induced systemic inflammatory syndrome. The immune response in sepsis is characterized by the activation of both proinflammatory and anti-inflammatory pathways. When sepsis occurs, the expression and activity of many inflammatory cytokines are markedly affected. Xenobiotic receptors are chemical-sensing transcription factors that play essential roles in the transcriptional regulation of drug-metabolizing enzymes (DMEs). Xenobiotic receptors mediate the functional crosstalk between sepsis and drug metabolism because the inflammatory cytokines released during sepsis can affect the expression and activity of xenobiotic receptors and thus impact the expression and activity of DMEs. Xenobiotic receptors in turn may affect the clinical outcomes of sepsis. This review focuses on the sepsis-induced inflammatory response and xenobiotic receptors such as pregnane X receptor (PXR), aryl hydrocarbon receptor (AHR), glucocorticoid receptor (GR), and constitutive androstane receptor (CAR), DMEs such as CYP1A, CYP2B6, CYP2C9, and CYP3A4, and drug transporters such as p-glycoprotein (P-gp), and multidrug resistance-associated protein (MRPs) that are affected by sepsis. Understanding the xenobiotic receptor-mediated effect of sepsis on drug metabolism will help to improve the safe use of drugs in sepsis patients and the development of new xenobiotic receptor-based therapeutic strategies for sepsis., Graphical abstract The functional crosstalk between sepsis and drug metabolism is mediated by xenobiotic receptors. The inflammatory cytokines released during sepsis can affect the expression and activity of xenobiotic receptors and thus impact the expression and activity of DMEs.Image 1

Our recent studies demonstrated that the natural product nobiletin (NOB) served as a promising multidrug resistance (MDR) reversal agent and improved the effectiveness of cancer chemotherapy in vitro. However, low aqueous solubility and difficulty in total synthesis limited its application as a therapeutic agent. To tackle these challenges, NOB was synthesized in a high yield by a concise route of six steps and fourteen derivatives were synthesized with remarkable solubility and efficacy. All the compounds showed improved sensitivity to paclitaxel (PTX) in P-glycoprotein (P-gp) overexpressing MDR cancer cells. Among them, compound 29d exhibited water solubility 280-fold higher than NOB. A drug-resistance A549/T xenograft model showed that 29d, at a dose of 50 mg/kg co-administered with PTX (15 mg/kg), inhibited tumor growth more effective than NOB and remarkably increased PTX concentration in the tumors via P-gp inhibition. Moreover, Western blot experiments revealed that 29d inhibited expression of NRF2, phosphorylated ERK and AKT in MDR cancer cells, thus implying 29d of multiple mechanisms to reverse MDR in lung cancer., Graphical abstract Compound 29d exhibited water solubility 280-fold higher than nobiletin (N). In a drug resistance A549/T xenograft model, 29d co-administered with paclitaxel (PTX) inhibited tumor growth more effective than N and remarkably increased PTX concentration in the tumors. Activated NRF2/PI3K/AKT pathways in MDR cancer cells were markedly inhibited by 29d and PTX.Image 1

Drug transportation is impeded by various barriers in the hypoxic solid tumor, resulting in compromised anticancer efficacy. Herein, a solid lipid monostearin (MS)-coated CaO2/MnO2 nanocarrier was designed to optimize doxorubicin (DOX) transportation comprehensively for chemotherapy enhancement. The MS shell of nanoparticles could be destroyed selectively by highly-expressed lipase within cancer cells, exposing water-sensitive cores to release DOX and produce O2. After the cancer cell death, the core-exposed nanoparticles could be further liberated and continue to react with water in the tumor extracellular matrix (ECM) and thoroughly release O2 and DOX, which exhibited cytotoxicity to neighboring cells. Small DOX molecules could readily diffuse through ECM, in which the collagen deposition was decreased by O2-mediated hypoxia-inducible factor-1 inhibition, leading to synergistically improved drug penetration. Concurrently, DOX-efflux-associated P-glycoprotein was also inhibited by O2, prolonging drug retention in cancer cells. Overall, the DOX transporting processes from nanoparticles to deep tumor cells including drug release, penetration, and retention were optimized comprehensively, which significantly boosted antitumor benefits., Graphical abstract Synergistic drug penetration, sufficient drug release, and prolonged drug retention were concurrently realized by a smart O2-generating nanocarrier, contributing to comprehensively optimized drug transportation and thereby improved chemotherapy.Image 1

Graphical abstract Ivermectin has powerful antitumor effects, including the inhibition of proliferation, metastasis, and angiogenic activity, in a variety of cancer cells. This may be related to the regulation of multiple signaling pathways by ivermectin through PAK1 kinase. On the other hand, ivermectin promotes programmed cancer cell death, including apoptosis, autophagy and pyroptosis. Ivermectin induces apoptosis and autophagy is mutually regulated. Interestingly, ivermectin can also inhibit tumor stem cells and reverse multidrug resistance and exerts the optimal effect when used in combination with other chemotherapy drugs., Highlights • Ivermectin effectively suppresses the proliferation and metastasis of cancer cells and promotes cancer cell death at doses that are nontoxic to normal cells. • Ivermectin shows excellent efficacy against conventional chemotherapy drug-resistant cancer cells and reverses multidrug resistance. • Ivermectin combined with other chemotherapy drugs or targeted drugs has powerful effects on cancer. • The structure of crosstalk centered on PAK1 kinase reveals the mechanism by which ivermectin regulates multiple signaling pathways. • Ivermectin has been used to treat parasitic diseases in humans for many years and can quickly enter clinical trials for the treatment of tumors., Ivermectin is a macrolide antiparasitic drug with a 16-membered ring that is widely used for the treatment of many parasitic diseases such as river blindness, elephantiasis and scabies. Satoshi ōmura and William C. Campbell won the 2015 Nobel Prize in Physiology or Medicine for the discovery of the excellent efficacy of ivermectin against parasitic diseases. Recently, ivermectin has been reported to inhibit the proliferation of several tumor cells by regulating multiple signaling pathways. This suggests that ivermectin may be an anticancer drug with great potential. Here, we reviewed the related mechanisms by which ivermectin inhibited the development of different cancers and promoted programmed cell death and discussed the prospects for the clinical application of ivermectin as an anticancer drug for neoplasm therapy.

Background Emerging evidence shows that severe COVID-19 can be complicated by a significant coagulopathy, that likely manifests in the form of both microthrombosis and venous thromboembolism (VTE). This recognition has led to the urgent need for practical guidance regarding prevention, diagnosis, and treatment of VTE. Methods A group of approved panelists developed key clinical questions by using the PICO (population, intervention, comparator, and outcome) format that addressed urgent clinical questions regarding the prevention, diagnosis and treatment of venous thromboembolism in patients with COVID-19. MEDLINE (via PubMed or Ovid), Embase and Cochrane Controlled Register of Trials were systematically searched for relevant literature and references were screened for inclusion. Validated evaluation tools were used to grade the level of evidence to support each recommendation. When evidence did not exist, guidance was developed based on consensus using the modified Delphi process. Results The systematic review and critical analysis of the literature based on13 PICO questions resulted in 22 statements. Very little evidence exists in the COVID-19 population. The panel thus used expert consensus and existing evidence-based guidelines to craft the guidance statements. Conclusions The evidence on the optimal strategies to prevent, diagnose, and treat venous thromboembolism in patients with COVID-19 is sparse, but rapidly evolving.

Highlights • Extracellular vesicles’ (EVs) role in breast tumor microenvironment and pre-metastatic niche development. • Breast cancer EV-mediated transmission of pro-metastatic and drug-resistant phenotypes. • Precision medicine with EVs as biomarkers and delivery vehicles for drug and anticancer genetic material., Breast cancer metastatic progression to critical secondary sites is the second leading cause of cancer-related mortality in women. While existing therapies are highly effective in combating primary tumors, metastatic disease is generally deemed incurable with a median survival of only 2, 3 years. Extensive efforts have focused on identifying metastatic contributory targets for therapeutic antagonism and prevention to improve patient survivability. Excessive breast cancer release of extracellular vesicles (EVs), whose contents stimulate a metastatic phenotype, represents a promising target. Complex breast cancer intercellular communication networks are based on EV transport and transference of molecular information is in bulk resulting in complete reprogramming events within recipient cells. Other breast cancer cells can acquire aggressive phenotypes, endothelial cells can be induced to undergo tubule formation, and immune cells can be neutralized. Recent advancements continue to implicate the critical role EVs play in cultivating a tumor microenvironment tailored to cancer proliferation, metastasis, immune evasion, and conference of drug resistance. This literature review serves to frame the role of EV transport in breast cancer progression and metastasis. The following five sections will be addressed: (1) Intercellular communication in developing a tumor microenvironment & pre-metastatic niche. (2) Induction of the epithelial-to-mesenchymal transition (EMT). (3). Immune suppression & evasion. (4) Transmission of drug resistance mechanisms. (5) Precision medicine: clinical applications of EVs.

In recent years, the coamorphous drug delivery system has been established as a promising formulation approach for delivering poorly water-soluble drugs. The coamorphous solid is a single-phase system containing an active pharmaceutical ingredient (API) and other low molecular weight molecules that might be pharmacologically relevant APIs or excipients. These formulations exhibit considerable advantages over neat crystalline or amorphous material, including improved physical stability, dissolution profiles, and potentially enhanced therapeutic efficacy. This review provides a comprehensive overview of coamorphous drug delivery systems from the perspectives of preparation, physicochemical characteristics, physical stability, in vitro and in vivo performance. Furthermore, the challenges and strategies in developing robust coamorphous drug products of high quality and performance are briefly discussed., Graphical abstract fx1

The anticancer drug temozolomide is the only drug with proven activity against high-grade gliomas and has therefore become a part of the standard treatment of these tumors. P-glycoprotein (P-gp; ABCB1) and breast cancer resistance protein (BCRP; ABCG2) are transport proteins, which are present at the blood-brain barrier and limit the brain uptake of substrate drugs. We have studied the effect of P-gp and BCRP on the pharmacokinetics and pharmacodynamics of temozolomide, making use of a comprehensive set of in vitro transport experiments and in vivo pharmacokinetic and antitumor efficacy experiments using wild-type, Abcg2−/−, Abcb1a/b−/−, and Abcb1a/b;Abcg2−/− mice. We here show that the combined deletion of Abcb1a/b and Abcg2 increases the brain penetration of temozolomide by 1.5-fold compared to wild-type controls (P < .001) without changing the systemic drug exposure. Moreover, the same increase was achieved when temozolomide was given to wild-type mice in combination with the dual P-gp/BCRP inhibitor elacridar (GF120918). The antitumor efficacy of temozolomide against three different intracranial tumor models was significantly enhanced when Abcb1a/b and Abcg2 were genetically deficient or pharmacologically inhibited in recipient mice. These findings call for further clinical testing of temozolomide in combination with elacridar for the treatment of gliomas, as this offers the perspective of further improving the antitumor efficacy of this already active agent.

Mesoporous silica nanoparticles (MSNs) are attracting increasing interest for potential biomedical applications. With tailored mesoporous structure, huge surface area and pore volume, selective surface functionality, as well as morphology control, MSNs exhibit high loading capacity for therapeutic agents and controlled release properties if modified with stimuli-responsive groups, polymers or proteins. In this review article, the applications of MSNs in pharmaceutics to improve drug bioavailability, reduce drug toxicity, and deliver with cellular targetability are summarized. Particularly, the exciting progress in the development of MSNs-based effective delivery systems for poorly soluble drugs, anticancer agents, and therapeutic genes are highlighted., Graphical abstract Mesoporous silica nanoparticles (MSNs) with unique properties have attracted increasing interest for biomedical applications. Particularly, MSNs have shown great potential to deliver poorly soluble drugs, anticancer agents, and therapeutic genes.fx1

Highlights • Combination of olaparib and photodynamic therapy is effective in reducing the number and clonogenic survival of ovarian cancer cells. • Photodynamic therapy using a lipidated photosensitizer reduces the selective advantage of olaparib-resistant ovarian cancer cells. • Photodynamic therapy potentiates the DNA-damaging effects of olaparib., P-glycoprotein (P-gp) is an adenosine triphosphate (ATP)-dependent drug efflux protein commonly associated with multidrug resistance in cancer chemotherapy. In this report, we used a dual-fluorescent co-culture model to study the population dynamics of the drug sensitive human ovarian cancer cell line (OVCAR-8-DsRed2) and its resistant subline that overexpresses P-gp (NCI/ADR-RES-EGFP) during the course of a photodynamic therapy (PDT)-olaparib combination regimen. Without treatment, OVCAR-8-DsRed2 cells grew more rapidly than the NCI/ADR-RES-EGFP cells. Olaparib treatment reduced the total number of cancer cells by 70±4% but selected for the resistant NCI/ADR-RES-EGFP population since olaparib is an efflux substrate for the P-gp pump. This study used the FDA-approved benzoporphyrin derivative (BPD) photosensitizer or its lipidated formulation ((16:0)LysoPC-BPD) to kill OVCAR-8 cells and reduce the likelihood that olaparib-resistant cells would have selective advantage. Three cycles of PDT effectively reduced the total cell number by 66±3%, while stabilizing the population ratio of sensitive and resistant cells at approximately 1:1. The combination of olaparib treatment and PDT enhanced PARP cleavage and deoxyribonucleic acid (DNA) damage, further decreasing the total cancer cell number down to 10±2%. We also showed that the combination of olaparib and (16:0)LysoPC-BPD-based PDT is up to 18-fold more effective in mitigating the selection of resistant NCI/ADR-RES-EGFP cells, compared to using olaparib and BPD-based PDT. These studies suggest that PDT may improve the effectiveness of olaparib, and the use of a lipidated photosensitizer formulation holds promise in overcoming cancer drug resistance.

Hepatic encephalopathy (HE) is a neurological complication of hepatic dysfunction and portosystemic shunting. It is highly prevalent in patients with cirrhosis and is associated with poor outcomes. New insights into the role of peripheral origins in HE have led to the development of innovative treatment strategies like faecal microbiota transplantation. However, this broadening of view has not been applied fully to perturbations in the central nervous system. The old paradigm that HE is the clinical manifestation of ammonia-induced astrocyte dysfunction and its secondary neuronal consequences requires updating. In this review, we will use the holistic concept of the neurogliovascular unit to describe central nervous system disturbances in HE, an approach that has proven instrumental in other neurological disorders. We will describe HE as a global dysfunction of the neurogliovascular unit, where blood flow and nutrient supply to the brain, as well as the function of the blood-brain barrier, are impaired. This leads to an accumulation of neurotoxic substances, chief among them ammonia and inflammatory mediators, causing dysfunction of astrocytes and microglia. Finally, glymphatic dysfunction impairs the clearance of these neurotoxins, further aggravating their effect on the brain. Taking a broader view of central nervous system alterations in liver disease could serve as the basis for further research into the specific brain pathophysiology of HE, as well as the development of therapeutic strategies specifically aimed at counteracting the often irreversible central nervous system damage seen in these patients. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).

Oral drug absorption is a process influenced by the physicochemical and biopharmaceutical properties of the drug and its inter-relationship with the gastrointestinal tract. Drug solubility, dissolution and permeability across intestinal barrier are the key parameters controlling absorption. This review provides an overview of the factors that affect drug absorption and the classification of a drug on the basis of solubility and permeability. The biopharmaceutical classification system (BCS) was introduced in early 90׳s and is a regulatory tool used to predict bioavailability problems associated with a new entity, thereby helping in the development of a drug product. Strategies to combat solubility and permeability issues are also discussed., Graphical abstract Bioavailability of a drug depends on physicochemical properties of the drug and physiological factors and dosage-related factors. Drug absorption occurs from the gut wall by passive diffusion, carrier-mediated uptake and paracellular transport. Several formulation strategies can be used to combat poor bioavailability.fx1

Polyethylene glycols (PEGs) in general use are polydisperse molecules with molecular weight (MW) distributed around an average value applied in their designation e.g., PEG 4000. Previous research has shown that PEGs can act as P-glycoprotein (P-gp) inhibitors with the potential to affect the absorption and efflux of concomitantly administered drugs. However, questions related to the mechanism of cellular uptake of PEGs and the exact role played by P-gp has not been addressed. In this study, we examined the mechanism of uptake of PEGs by MDCK-mock cells, in particular, the effect of MW and interaction with P-gp by MDCK-hMDR1 and A549 cells. The results show that: (a) the uptake of PEGs by MDCK-hMDR1 cells is enhanced by P-gp inhibitors; (b) PEGs stimulate P-gp ATPase activity but to a much lesser extent than verapamil; and (c) uptake of PEGs of low MW (5000 Da) occurs by a combination of passive diffusion and caveolae-mediated endocytosis. These findings suggest that PEGs can engage in P-gp-based drug interactions which we believe should be taken into account when using PEGs as excipients and in PEGylated drugs and drug delivery systems., Graphical abstract PEGs are taken up by cells and act as P-gp substrates. Low molecular weight (MW) PEGs cross cell membranes by passive diffusion, whereas those high MW PEGs enter cells by a combination of passive diffusion and caveolae-mediated endocytosis.Image 1

���������� ������ ������������ ���������������������� ������ ���������������� ������ �������������������������������� �������������� ���� ���������������� �������������� ������������������ �������������� ���� ������ ���������������� �������������������������� ������ ���������������� ������ ������������������������ ��450 ������/�� ������������������ ������ ���������������������� ���� �������������� �������� ���������������� ���� ������������������������ ��������������. ���� ������������������������ �������������� ������������������ ������ ���������������� ���������������������� �������������������������� ������ �������������� ������ �������������� ������������ �������� ������������������������������. �������������� ������������������ ������ ���������������� ������ ������������ �������������������������� ������������ ������������ �������������������������� ������ ABCB1 ������ CYP2D6 �������� ���������������� ������ ������������������ �������������� ������ �������������� ������ ������������������������ �� ���������������������� ��������������������, ���������������������� ������ ������������ ������ ���� �������������� ������������������������������ ������������ �������������������������� ������ ���������������� ABCB1 ������ CYP2C19, �������� �������� ���������������� ��������������. ���������������� ����������������, ������������������ ������������������, ���� ���������������� ������������������������ ������ ���������� ������������������������������ ��������������������, ������ ���������������� ���������� �������������� ���� ������ �������������� �������� (���������������������������� ��������������) ������������������������������ ������ ������������. �� �������������������� ������ �������� ���������������������������� ������ CYP2C19*2 ������ *17 �������������������������������� ���� �������������� ���������������� RLFP-PCR. ���� ������������������ ������ ���� ABCB1 3435C>T (rs1045642) �������� �������������� ������ ���������������������� ������������. �� ���������������������� �������������������� ������ �������� ������������, ������ �������������������� ���� ������ ���������������� ������ CYP2C19, ���������������������� �������������� ���� ������ �������������� ������ CPIC. �� ���������������� ������ ������������������ ������ �������� ������������������������ ������ ������ ������ ������������������ ��������, ������������������ ������ ������������������ ���� ������ �������������� �������������� ������ ������������������ ������������������ �������� ������ ���������������� ������ ���������������� (PANSSbase), ���� ������ �������������� ������ �������� ������ ���������������� ������������������ ������������������ (PANSSdif),������ ���� ������ �������� ���������������� �������� �������������������������� ���������������� ������ ����������������������, �������������������� ���� ������������������ ������������������������������ (CPZeq). ���������������������� ������ �������������������� ������������������ �������������������������� ������������ ������ ���������������������� �������������������� ������ CYP2C19 ������ ������ �������������������������� ������ ABCB1, �� ���������� ���������������� ���� ������������������ ������ ������������ ������ ���������������������� ������ �������������� �������� ������ ���������������� �������� ������������ ������ ������ ���������������� �������� ���������������� ������ �������������� ���� ���������������� ������������������������., Pharmacogenetic studies have failed, so far, to provide solid evidence supporting the effect of CYP450 and/ or protein pump gene polymorphisms on response to antipsychotic drugs. Most studies investigate the effect of individual polymorphisms while ignoring their possible interactions. Having detected a possible interaction between common ABCB1 and CYP2D6 polymorphisms in affecting the response of patients suffering from schizophrenia and related disorders, we have extended our search to the interaction between ABCB1 and CYP2C19 polymorphisms in the same patient group. Ninety Greek patients suffering from schizophrenia and other psychotic disorders, and treated with antipsychotic drugs on a per need basis (naturalistic setting) were included in this study. Genotyping of the CYP2C19*2 and *17 polymorphisms was accomplished with established RLFP-PCR methods. ABCB1 3435C>T (rs1045642) genotypes were already known from a previous study. Patient CYP2C19 metabolizer status was according to CPIC criteria. Genotype distributions of individual polymorphisms and their combinations were tested for association with the positive and negative syndrome scale at presentation (PANSSbase), its difference following four weeks of treatment (PANSSdif), and the average daily administration of antipsychotic drugs normalized to chlorpromazine equivalents (CPZeq). We have detected a statistically significant interaction between the CYP2C19 metabolizer status and the ABCB1 gene polymorphisms, affecting the intensity of symptoms at presentation in whole patient group and the response to treatment of patients diagnosed with schizophrenia.

The expression and function of some xenobiotic transporters vary according to the time of the day, causing the dosing time-dependent changes in drug disposition and toxicity. P-glycoprotein (P-gp), encoded by the ABCB1 gene, is highly expressed in the kidneys and functions in the renal elimination of various drugs. The elimination of several P-gp substrates was demonstrated to vary depending on administration time, but the underlying mechanism remains unclear. We found that adenosine deaminase acting on RNA (ADAR1) was involved in the circadian regulation of P-gp expression in human renal proximal tubular epithelial cells (RPTECs). After synchronization of the cellular circadian clock by dexamethasone treatment, the expression of P-gp exhibited a significant 24-h oscillation in RPTECs, but this oscillation was disrupted by the downregulation of ADAR1. Although ADAR1 catalyzes adenosine-to-inosine (A-to-I) RNA editing in double-stranded RNA substrates, no significant ADAR1-regulated editing sites were detected in the human ABCB1 transcripts in RPTECs. On the other hand, downregulation of ADAR1 induced alternative splicing in intron 27 of the human ABCB1 gene, resulting in the production of retained intron transcripts. The aberrant spliced transcript was sensitive to nonsense-mediated mRNA decay, leading to the decreased stability of ABCB1 mRNA and prevention of the 24-h oscillation of P-gp expression. These findings support the notion that ADAR1-mediated regulation of alternative splicing of the ABCB1 gene is a key mechanism of circadian expression of P-gp in RPTECs, and the regulatory mechanism may underlie the dosing time-dependent variations in the renal elimination of P-gp substrates.

The kidney is a vital organ for the elimination of therapeutic drugs and their metabolites. Renal drug transporters, which are primarily located in the renal proximal tubules, play an important role in tubular secretion and reabsorption of drug molecules in the kidney. Tubular secretion is characterized by high clearance capacities, broad substrate specificities, and distinct charge selectivity for organic cations and anions. In the past two decades, substantial progress has been made in understanding the roles of transporters in drug disposition, efficacy, toxicity and drug–drug interactions (DDIs). In the kidney, several transporters are involved in renal handling of organic cation (OC) and organic anion (OA) drugs. These transporters are increasingly recognized as the target for clinically significant DDIs. This review focuses on the functional characteristics of major human renal drug transporters and their involvement in clinically significant DDIs., Graphical abstract Renal drug transporters, expressed in the basolateral and apical membrane of renal proximal tubules, play an important role in tubular secretion and reabsorption of drug molecules in the kidney. These transporters are increasingly recognized as the target for clinically significant drug–drug interactions.

Oral administration is the most commonly used route for drug treatment. Intestinal cytochrome P450 (CYP)-mediated metabolism can eliminate a large proportion of some orally administered drugs before they reach systemic circulation, while leaving the passage of other drugs unimpeded. A better understanding of the ability of intestinal P450 enzymes to metabolize various clinical drugs in both humans and preclinical animal species, including the identification of the CYP enzymes expressed, their regulation, and the relative importance of intestinal metabolism compared to hepatic metabolism, is important for improving bioavailability of current drugs and new drugs in development. Here, we briefly review the expression of drug-metabolizing P450 enzymes in the small intestine of humans and several preclinical animal species, and provide an update of the various factors or events that regulate intestinal P450 expression, including a cross talk between the liver and the intestine. We further compare various clinical and preclinical approaches for assessing the impact of intestinal drug metabolism on bioavailability, and discuss the utility of the intestinal epithelium–specific NADPH-cytochrome P450 reductase-null (IECN) mouse as a useful model for studying in vivo roles of intestinal P450 in the disposition of orally administered drugs., Graphical abstract A better understanding of the ability of intestinal P450 enzymes to metabolize various drugs is important for improving drug bioavailability. The intestinal epithelium-specific P450 reductase-null mouse model can be utilized to facilitate studies on the in vivo roles of intestinal P450 enzymes in the disposition of orally administered drugs. fx1

The pregnane X receptor (PXR) plays an important and diverse role in mediating xenobiotic induction of drug-metabolizing enzymes and transporters. Several protein isoforms of PXR exist, and they have differential transcriptional activity upon target genes; transcript variants 3 (PXR3) and 4 (PXR4) do not induce target gene expression, whereas transcript variants 1 (PXR1) and 2 (PXR2) respond to agonist by activating target gene expression. PXR protein variants also display differences in protein–protein interactions; PXR1 interacts with p53, whereas PXR3 does not. Furthermore, the transcript variants of PXR that encode these protein isoforms are differentially regulated by methylation and deletions in the respective promoters of the variants, and their expression differs in various human cancers and also in cancerous tissue compared to adjacent normal tissues. PXR1 and PXR4 mRNA are downregulated by methylation in cancerous tissue and have divergent effects on cellular proliferation when ectopically overexpressed. Additional detailed and comparative mechanistic studies are required to predict the effect of PXR transcript variant expression on carcinogenesis, therapeutic response, and the development of toxicity., Graphical abstract PXR induces drug-metabolizing enzymes and transporters, and has multiple transcript variants, such as PXR1, PXR2, PXR3, and PXR4, which respond to agonists, interact with other proteins, and affect cellular function differently. Further studies are required to predict the effect of PXR variants on carcinogenesis, therapeutic response, and toxicity. fx1

The anaplastic lymphoma kinase (ALK) fusion oncogene is observed in 3%–5% of non-small cell lung cancer (NSCLC). Crizotinib and ceritinib, a next-generation ALK tyrosine kinase inhibitor (TKI) active against crizotinib-refractory patients, are clinically available for the treatment of ALK-rearranged NSCLC patients, and multiple next-generation ALK-TKIs are currently under clinical evaluation. These ALK-TKIs exhibit robust clinical activity in ALK-rearranged NSCLC patients; however, the emergence of ALK-TKI resistance restricts the therapeutic effect. To date, various secondary mutations or bypass pathway activation-mediated resistance have been identified, but large parts of the resistance mechanism are yet to be identified. Here, we report the discovery of p-glycoprotein (P-gp/ABCB1) overexpression as a ceritinib resistance mechanism in ALK-rearranged NSCLC patients. P-gp exported ceritinib and its overexpression conferred ceritinib and crizotinib resistance, but not to PF-06463922 or alectinib, which are next-generation ALK inhibitors. Knockdown of ABCB1 or P-gp inhibitors sensitizes the patient-derived cancer cells to ceritinib, in vitro and in vivo. P-gp overexpression was identified in three out of 11 cases with in ALK-rearranged crizotinib or ceritinib resistant NSCLC patients. Our study suggests that alectinib, PF-06463922, or P-gp inhibitor with ceritinib could overcome the ceritinib or crizotinib resistance mediated by P-gp overexpression., Highlights • Ceritinib resistant patient-derived cancer cells overexpress P-gp without having mutation in ALK and other major oncogenes. • P-gp overexpression conferred the resistance to ceritinib and crizotinib but not to alectinib and PF-06463922. • Ceritinib is a substrate of P-gp, and P-gp-inhibitors or knockdown of P-gp reversed ceritinib resistance. • P-gp overexpression was observed in 3 out of 11 crizotinib- or ceritinib-resistant ALK-rearranged NSCLC patients. For treatment of ALK-rearranged NSCLC, two ALK-TKIs, crizotinib and ceritinib are currently in use, but the emergence of acquired resistance limits the efficacy of ALK-TKIs. Except for the resistance-associated mutations in ALK, ALK-TKIs resistance mechanisms are still largely unknown. Here we identified P-gp overexpression mediating resistance in three ceritinib-resistant ALK-rearranged NSCLC patients. P-gp overexpression conferred ceritinib and crizotinib resistance but did not confer alectinib and PF-06463922 resistance, and treatment using P-gp inhibitor with ceritinib, or alectinib- or PF-06463922- monotherapy overcame the resistance, suggesting that P-gp expression could be an important determinant in the future treatment strategies.