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Expert Opinion on Drug Metabolism &... May 2021: Expression of P-glycoprotein (P-gp) increases toward the distal small intestine, implying that the duodenum is the preferential absorption site for P-gp substrate... (Review)
Review
: Expression of P-glycoprotein (P-gp) increases toward the distal small intestine, implying that the duodenum is the preferential absorption site for P-gp substrate drugs. Oral bioavailability of poorly soluble P-gp substrate drugs is low and varied but increases with high-fat meals that supply lipoidal components and bile in the duodenum.: Absorption properties of P-gp substrate drugs along with factors and oral dosage formulations affecting their solubility and bioavailability were reviewed with PubMed literature searches. An overview is provided from the viewpoint of the 'spring-and-parachute approach' that generates supersaturation of poorly soluble P-gp substrate drugs.: The oral bioavailability of P-gp substrate drugs is difficult to predict because of their low solubility, preferential absorption sites, and overlapping substrate specificities with CYP3A4, along with the scattered intestinal P-gp expression/function. To attain high and steady oral bioavailability of poorly soluble P-gp substrate drugs, physicochemical modification of drugs to improve solubility, or oral dosage formulations that generate long-lasting supersaturation in the duodenum, is preferred. In particular, supersaturable lipid-based drug delivery systems that can increase passive diffusion and/or lymphatic absorption are effective and applicable to many poorly soluble P-gp substrate drugs.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Administration, Oral; Animals; Biological Availability; Chemistry, Pharmaceutical; Drug Delivery Systems; Humans; Intestinal Absorption; Lipids; Pharmaceutical Preparations; Solubility
PubMed: 33703995
DOI: 10.1080/17425255.2021.1902986 -
Epilepsy & Behavior : E&B Aug 2021Sudden unexpected death in epilepsy (SUDEP) is the major cause of death that affects patients with epilepsy. The risk of SUDEP increases according to the frequency and... (Review)
Review
Sudden unexpected death in epilepsy (SUDEP) is the major cause of death that affects patients with epilepsy. The risk of SUDEP increases according to the frequency and severity of uncontrolled seizures; therefore, SUDEP risk is higher in patients with refractory epilepsy (RE), in whom most antiepileptic drugs (AEDs) are ineffective for both seizure control and SUDEP prevention. Consequently, RE and SUDEP share a multidrug resistance (MDR) phenotype, which is mainly associated with brain overexpression of ABC-transporters such as P-glycoprotein (P-gp). The activity of P-gp can also contribute to membrane depolarization and affect the normal function of neurons and cardiomyocytes. Other molecular regulators of membrane potential are the inwardly rectifying potassium channels (Kir), whose genetic variants have been related to both epilepsy and heart dysfunctions. Although it has been suggested that dysfunctions of the cardiac, respiratory, and brainstem arousal systems are the causes of SUDEP, the molecular basis for explaining its dysfunctions remain unknown. In rats, repetitive seizures or status epilepticus induced high expression of P-gp and loss Kir expression in the brain and heart, and promoted membrane depolarization, malignant bradycardia, and the high rate of mortality. Here we reviewed clinical and experimental evidences suggesting that abnormal expression of depolarizing/repolarizing factors as P-gp and Kir could favor persistent depolarization of membranes without any rapid functional recovery capacity. This condition induced by convulsive stress could be the molecular mechanism leading to acquired severe bradycardia, as an ineffective heart response generating the appropriate scenario for SUDEP development. This article is part of the Special Issue "NEWroscience 2018".
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Death, Sudden; Epilepsy; Humans; Potassium; Rats; Risk Factors; Sudden Unexpected Death in Epilepsy
PubMed: 31706919
DOI: 10.1016/j.yebeh.2019.106590 -
Molecular Oncology Jan 2023Chemotherapy resistance is a persistent clinical problem in relapsed high-risk neuroblastomas. We tested a panel of 15 drugs for sensitization of neuroblastoma cells to...
Chemotherapy resistance is a persistent clinical problem in relapsed high-risk neuroblastomas. We tested a panel of 15 drugs for sensitization of neuroblastoma cells to the conventional chemotherapeutic vincristine, identifying tariquidar, an inhibitor of the transmembrane pump P-glycoprotein (P-gp/ABCB1), and the ERBB family inhibitor afatinib as the top resistance breakers. Both compounds were efficient in sensitizing neuroblastoma cells to vincristine in trypan blue exclusion assays and in inducing apoptotic cell death. The evaluation of ERBB signaling revealed no functional inhibition, that is, dephosphorylation of the downstream pathways upon afatinib treatment but direct off-target interference with P-gp function. Depletion of ABCB1, but not ERRB4, sensitized cells to vincristine treatment. P-gp inhibition substantially broke vincristine resistance in vitro and in vivo (zebrafish embryo xenograft). The analysis of gene expression datasets of more than 50 different neuroblastoma cell lines (primary and relapsed) and more than 160 neuroblastoma patient samples from the pediatric precision medicine platform INFORM (Individualized Therapy For Relapsed Malignancies in Childhood) confirmed a pivotal role of P-gp specifically in neuroblastoma resistance at relapse, while the ERBB family appears to play a minor part.
Topics: Animals; Humans; ATP Binding Cassette Transporter, Subfamily B, Member 1; Vincristine; Afatinib; Zebrafish; Drug Resistance, Neoplasm; Neuroblastoma; ATP Binding Cassette Transporter, Subfamily B; ErbB Receptors; Recurrence; Cell Line, Tumor
PubMed: 36181342
DOI: 10.1002/1878-0261.13318 -
AAPS PharmSciTech Jan 2022Significant research efforts have been devoted to unraveling the mystery of P-glycoprotein(P-gp) in drug delivery applications. The efflux membrane transporter P-gp is... (Review)
Review
Significant research efforts have been devoted to unraveling the mystery of P-glycoprotein(P-gp) in drug delivery applications. The efflux membrane transporter P-gp is widely distributed in the body and accountable for restricting drug absorption and bioavailability. For these reasons, it is the primary cause of developing multidrug resistance (MDR) in most drug delivery applications. Therefore, P-gp inhibitors must be explored to address MDR and the low bioavailability of therapeutic substrates. Several experimental models in kinetics and dynamic studies identified the sensitivity of drug molecules and excipients as a P-gp inhibitor. In this review, we aimed to emphasize nonionic surface-active agents for effective reversal of P-gp inhibition. As it is inert, non-toxic, noncharged, and quickly reaching the cytosolic lipid membrane (the point of contact with P-gp efflux protein) enables it to be more efficient as P-gp inhibitors. Moreover, nonionic surfactant improves drug absorption and bioavailability through the various mechanism, involving (i) association of drug with surfactant improves solubilization, facilitating its cell penetration and absorption; (ii) weakening the lateral membrane packing density, facilitating the passive drug influx; and (iii) inhibition of the ATP binding cassette of transporter P-glycoprotein. The application of nonionic surfactant as P-gp inhibitors is well established and supported by various experiments. Altogether, herein, we have primarily focused on various nonionic surfactants and their development strategies to conquer the MDR-causing effects of P-gp efflux protein in drug delivery. Graphical Abstract.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Drug Resistance, Multiple; Pharmaceutical Preparations; Surface-Active Agents
PubMed: 35043278
DOI: 10.1208/s12249-022-02211-1 -
Drug Development Research Jun 2022P-glycoprotein (P-gp) is a transporter protein that is come under the ATP binding cassette family of proteins. It is situated on the surface of the intestine epithelium,... (Review)
Review
P-glycoprotein (P-gp) is a transporter protein that is come under the ATP binding cassette family of proteins. It is situated on the surface of the intestine epithelium, where P-gp substrate binds to the transporter and is pumped into the intestine lumen by the ATP-driven energy-dependent process. In this review, we summarize the role of the P-gp efflux transporter situated on the intestine, the clinical importance of P-gp related drug interactions, and approaches to minimize the effect of P-gp in drug transport. This review also focuses on the impact of P-gp on the bioavailability of the orally administered drug. Many drug's oral bioavailabilities can improve by concomitant use of P-gp inhibitors. Multidrug resistance are reduced by using some naturally occurring compounds obtained from plants and several synthetic P-gp inhibitors. Formulation strategies, one of the most important approaches to mimic the P-gp transporter's action, finally enhancing the oral bioavailability of the drug by inhibiting its P-gp efflux. Vitamin E TPGS, Gelucire 44/14 and other pharmaceutical/formulation excipients inhibit the P-gp efflux. A prodrug approach might be a useful strategy to overcome drug resistance. Prodrug helps to enhance the solubility or alter the pharmacokinetic properties but does not diminish the pharmacological action.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Adenosine Triphosphate; Biological Availability; Prodrugs
PubMed: 35103340
DOI: 10.1002/ddr.21918 -
Journal of Controlled Release :... Jul 2021P-Glycoprotein serves as a gatekeeper in the blood-brain-barrier wherein, it shows a vital part in the elimination of xenobiotics, drugs, foreign molecules etc. and... (Review)
Review
P-Glycoprotein serves as a gatekeeper in the blood-brain-barrier wherein, it shows a vital part in the elimination of xenobiotics, drugs, foreign molecules etc. and guards the central nervous system from infections and external toxic molecules by functioning as an efflux transporter. It plays an essential role in various brain-related conditions like Parkinsonism, Alzheimer's disease, depression, cancer, etc. and terminates the entry of therapeutic agents across blood-brain-barrier which remains a significant challenge serving as major hindrance in pharmacotherapy of disease. The physiological structure and topology of P-glycoprotein and its relation with blood-brain-barrier and central nervous system gives an idea for targeting nanocarriers across the barrier into brain. This review article provides an overview of current understanding of the nanoformulations-based P-gp trafficking strategies like nanocarriers, stem cell therapy, drugs, substrates, polymeric materials, chemical compounds as well as naturally occurring active constituents for improving drug transport in brain across blood-brain-barrier and contributing in effective nanotherapeutic development for treatment of CNS disorders.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Alzheimer Disease; Biological Transport; Blood-Brain Barrier; Brain; Humans
PubMed: 34087246
DOI: 10.1016/j.jconrel.2021.05.046 -
Fish Physiology and Biochemistry Oct 2022The role of the blood-brain barrier ATP-binding cassette protein transporter P-glycoprotein (P-gp) in protecting zebrafish (Danio rerio) from the central nervous system...
The role of the blood-brain barrier ATP-binding cassette protein transporter P-glycoprotein (P-gp) in protecting zebrafish (Danio rerio) from the central nervous system neurotoxicant ivermectin (IVM, 22,23-dihydroavermectin B1a + 22,23-dihydroavermectin B1b) was examined in the absence and presence of the competitive inhibitor cyclosporin A (CsA). Zebrafish injected intraperitoneally with 1, 2, 5, or 10 µmol/kg IVM exhibited mortality 30 min following administration at the highest dose. At sublethal doses > 1 µmol/kg, IVM altered the swimming performance, exploratory behaviour, motor coordination, escape response and olfactory response in exposed fish. When fish were exposed to IVM in the presence of CsA, alterations in swimming and behaviours increased significantly and at the highest IVM/CsA ratio resulted in a complete lack of exploratory and olfactory behaviours. In separate experiments, fish were either fed or fasted, and the effects of IVM and CsA administration were examined. The effects of IVM administration and the exacerbated effects seen with CsA co-administration were not affected by fasting. This study provides evidence that P-gp provides a protective role in the BBB of fish against environmental neurotoxicants. The results also show that P-gp activity is maintained even under conditions of food deprivation, suggesting that this chemical defence system is prioritized over other energy expenditures during diet limitation.
Topics: Animals; Ivermectin; ATP Binding Cassette Transporter, Subfamily B, Member 1; Zebrafish; Cyclosporine; Fasting; ATP Binding Cassette Transporter, Subfamily B; Adenosine Triphosphate
PubMed: 36006557
DOI: 10.1007/s10695-022-01111-2 -
International Journal of Molecular... Feb 2023Acute myeloid leukemia (AML) remains an insidious neoplasm due to the percentage of patients who develop resistance to both classic chemotherapy and emerging drugs.... (Review)
Review
Acute myeloid leukemia (AML) remains an insidious neoplasm due to the percentage of patients who develop resistance to both classic chemotherapy and emerging drugs. Multidrug resistance (MDR) is a complex process determined by multiple mechanisms, and it is often caused by the overexpression of efflux pumps, the most important of which is P-glycoprotein (P-gp). This mini-review aims to examine the advantages of using natural substances as P-gp inhibitors, focusing on four molecules: phytol, curcumin, lupeol, and heptacosane, and their mechanism of action in AML.
Topics: Humans; ATP Binding Cassette Transporter, Subfamily B, Member 1; Curcumin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Leukemia, Myeloid, Acute
PubMed: 36835550
DOI: 10.3390/ijms24044140 -
Proceedings. Biological Sciences May 2022Pesticides remain one of the most effective ways of controlling agricultural and public health insects, but much is still unknown regarding how these compounds reach...
Pesticides remain one of the most effective ways of controlling agricultural and public health insects, but much is still unknown regarding how these compounds reach their targets. Specifically, the role of ABC transporters in pesticide absorption and excretion is poorly understood, especially compared to the detailed knowledge about mammalian systems. Here, we present a comprehensive characterization of pesticide transporters in the model insect . An RNAi screen was performed, which knocked down individual ABCs in specific epithelial tissues and examined the subsequent changes in sensitivity to the pesticides spinosad and fipronil. This implicated a novel ABC drug transporter, in spinosad transport, but also highlighted the P-glycoprotein orthologue as the most impactful ABC in terms of chemoprotection. Further characterization of the P-glycoprotein family was performed via transgenic overexpression and immunolocalization, finding that and play enigmatic roles in pesticide toxicology perhaps determined by their different subcellular localizations within the midgut. Lastly, transgenic lines expressing P-glycoprotein from the major malaria vector were used to establish a system for characterization of this transporter in non-model insects. This study provides the basis for establishing as a model for toxicology research on drug transporters.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Animals; Animals, Genetically Modified; Anopheles; Drosophila melanogaster; Insecticide Resistance; Insecticides; Malaria; Mammals; Mosquito Vectors; Pesticides
PubMed: 35582794
DOI: 10.1098/rspb.2022.0625 -
Transplantation Feb 2023. Transplant recipients may develop rejection despite having adequate tacrolimus whole blood predose concentrations (C 0 ). The intra-immune cellular concentration is...
BACKGROUND
. Transplant recipients may develop rejection despite having adequate tacrolimus whole blood predose concentrations (C 0 ). The intra-immune cellular concentration is potentially a better target than C 0 . However, little is known regarding intracellular tacrolimus concentration in T-lymphocytes and monocytes. We investigated the tacrolimus concentrations in both cell types and their relation with the expression and activity of FK-binding protein (FKBP)-12 and P-glycoprotein (P-gp).
METHODS
. T-lymphocytes and monocytes were isolated from kidney transplant recipients followed by intracellular tacrolimus concentration measurement. FKBP-12 and P-gp were quantified with Western blot, flow cytometry, and the Rhodamine-123 assay. Interleukin-2 and interferon-γ in T-lymphocytes were measured to quantify the effect of tacrolimus.
RESULTS
. Tacrolimus concentration in T-lymphocytes was lower than in monocytes (15.3 [8.5-33.4] versus 131.0 [73.5-225.1] pg/million cells; P < 0.001). The activity of P-gp (measured by Rhodamine-123 assay) was higher in T-lymphocytes than in monocytes. Flow cytometry demonstrated a higher expression of P-gp (normalized mean fluorescence intensity 1.5 [1.2-1.7] versus 1.2 [1.1-1.4]; P = 0.012) and a lower expression of FKBP-12 (normalized mean fluorescence intensity 1.3 [1.2-1.7] versus 1.5 [1.4-2.0]; P = 0.011) in T-lymphocytes than monocytes. Western blot confirmed these observations. The addition of verapamil, a P-gp inhibitor, resulted in a 2-fold higher intra-T-cell tacrolimus concentration. This was accompanied by a significantly fewer cytokine-producing cells.
CONCLUSIONS
. T-lymphocytes have a higher activity of P-gp and lower concentration of the FKBP-12 compared with monocytes. This explains the relatively lower tacrolimus concentration in T-lymphocytes. The addition of verapamil prevents loss of intracellular tacrolimus during the cell isolation process and is required to ensure adequate intracellular concentration measurement.
Topics: Humans; Tacrolimus; Immunosuppressive Agents; T-Lymphocytes; ATP Binding Cassette Transporter, Subfamily B, Member 1; Kidney Transplantation; Monocytes; Carrier Proteins; Transplant Recipients; Tacrolimus Binding Protein 1A; ATP Binding Cassette Transporter, Subfamily B; Verapamil; Rhodamines
PubMed: 36070572
DOI: 10.1097/TP.0000000000004287