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Clinical Pharmacokinetics Jun 2020Understanding transporter-mediated drug-drug interactions (DDIs) for investigational agents is important during drug development to assess DDI liability, its clinical... (Review)
Review
Understanding transporter-mediated drug-drug interactions (DDIs) for investigational agents is important during drug development to assess DDI liability, its clinical relevance, and to determine appropriate DDI management strategies. P-glycoprotein (P-gp) is an efflux transporter that influences the pharmacokinetics (PK) of various compounds. Assessing transporter induction in vitro is challenging and is not always predictive of in vivo effects, and hence there is a need to consider clinical DDI studies; however, there is no clear guidance on when clinical evaluation of transporter induction is required. Furthermore, there is no proposed list of index transporter inducers to be used in clinical studies. This review evaluated DDI studies with known P-gp inducers to better understand the mechanism and site of P-gp induction, as well as the magnitude of induction effect on the exposure of P-gp substrates. Our review indicates that P-gp and cytochrome P450 (CYP450) enzymes are co-regulated via the pregnane xenobiotic receptor (PXR) and the constitutive androstane receptor (CAR). The magnitude of the decrease in substrate drug exposure by P-gp induction is generally less than that of CYP3A. Most P-gp inducers reduced total bioavailability with a minor impact on renal clearance, despite known expression of P-gp at the apical membrane of the kidney proximal tubules. Rifampin is the most potent P-gp inducer, resulting in an average reduction in substrate exposure ranging between 20 and 67%. For other inducers, the reduction in P-gp substrate exposure ranged from 12 to 42%. A lower reduction in exposure of the P-gp substrate was observed with a lower dose of the inducer and/or if the administration of the inducer and substrate was simultaneous, i.e. not staggered. These findings suggest that clinical evaluation of the impact of P-gp inducers on the PK of investigational agents that are substrates for P-gp might be warranted only for compounds with a relatively steep exposure-efficacy relationship.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Interactions; Humans; Membrane Transport Proteins; Pharmaceutical Preparations
PubMed: 32052379
DOI: 10.1007/s40262-020-00867-1 -
International Journal of Molecular... Nov 2022Maintenance of the tightly regulated homeostatic environment of the brain is facilitated by the blood-brain barrier (BBB). P-glycoprotein (P-gp), an ATP-binding cassette... (Review)
Review
Maintenance of the tightly regulated homeostatic environment of the brain is facilitated by the blood-brain barrier (BBB). P-glycoprotein (P-gp), an ATP-binding cassette transporter, is expressed on the luminal surface of the endothelial cells in the BBB, and actively exports a wide variety of substrates to limit exposure of the vulnerable brain environment to waste buildup and neurotoxic compounds. Downregulation of P-gp expression and activity at the BBB have been reported with ageing and in neurodegenerative diseases. Upregulation of P-gp at the BBB contributes to poor therapeutic outcomes due to altered pharmacokinetics of CNS-acting drugs. The regulation of P-gp is highly complex, but unravelling the mechanisms involved may help the development of novel and nuanced strategies to modulate P-gp expression for therapeutic benefit. This review summarises the current understanding of P-gp regulation in the brain, encompassing the transcriptional, post-transcriptional and post-translational mechanisms that have been identified to affect P-gp expression and transport activity.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Endothelial Cells; ATP Binding Cassette Transporter, Subfamily B; Brain; Blood-Brain Barrier; Central Nervous System Agents
PubMed: 36498995
DOI: 10.3390/ijms232314667 -
FEBS Letters Dec 2020The levels of amyloid peptides in the brain are regulated by a clearance pathway from neurons to the blood-brain barrier. The first step is thought to involve diffusion... (Review)
Review
The levels of amyloid peptides in the brain are regulated by a clearance pathway from neurons to the blood-brain barrier. The first step is thought to involve diffusion from the plasma membrane to the interstitium. However, amyloid peptides are hydrophobic and avidly intercalate within membranes. The ABC transporter P-glycoprotein is implicated in the clearance of amyloid peptides across the blood-brain, but its role at neurons is undetermined. We here propose that P-glycoprotein mediates 'exit' of amyloid peptides from neurons. Indeed, amyloid peptides have physicochemical similarities to substrates of P-glycoprotein, but their larger size represents a conundrum. This review probes the plausibility of a mechanism for amyloid peptide transport by P-glycoprotein exploiting evolving biochemical and structural models.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Amyloid beta-Peptides; Animals; Endothelial Cells; Humans; Neurons
PubMed: 33022784
DOI: 10.1002/1873-3468.13951 -
Biological & Pharmaceutical Bulletin 2021From the viewpoint of drug discovery, it is an important issue to elucidate the drug permeability at the human central nervous system (CNS) barriers and the molecular... (Review)
Review
From the viewpoint of drug discovery, it is an important issue to elucidate the drug permeability at the human central nervous system (CNS) barriers and the molecular mechanisms in the cells forming CNS barriers especially during CNS diseases. I introduced quantitative proteomics techniques into the blood-brain barrier (BBB) study, then quantitatively investigated the transport system at the human BBB and clarified the quantitative differences in protein expression levels and functions of transporters and receptors between animals and humans, or in vitro and in vivo. Based on the difference in the absolute expression level of transporters between in vitro and in vivo, I demonstrated that the drug efflux activity of P-glycoprotein (P-gp) at in vivo BBB can be accurately reconstructed from the in vitro system, not only in mouse models but also monkeys similar to humans and pathological conditions. Furthermore, I discovered Claudin-11 as another tight junction molecule expressed at the CNS barriers, and clarified that it contributes to the disruption of the CNS barriers in multiple sclerosis. Furthermore, it was also elucidated that the P-gp dysfunction causes excessive brain entry of glucocorticoid which causes a nerve damage in cerebral infarct, and it can be suppressed by targeting Abl/Src kinases. These suggest that targeting the tight junctions and transporters, which are important molecules at the CNS barriers, would potentially lead to the treatment of CNS diseases. In this review, I would like to introduce a new CNS barrier study opened by quantitative proteomics research.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Blood-Brain Barrier; Cerebral Infarction; Claudins; Drug Discovery; Humans; Multiple Sclerosis; Oxidative Stress; Proteomics; Tight Junctions
PubMed: 33790097
DOI: 10.1248/bpb.b21-00001 -
Biological & Pharmaceutical Bulletin 2018This review deals with recent advances in studies on P-glycoprotein (P-gp) and its expression regulators, focusing especially on our own research. Firstly, we describe... (Review)
Review
This review deals with recent advances in studies on P-glycoprotein (P-gp) and its expression regulators, focusing especially on our own research. Firstly, we describe findings demonstrating that the distribution of P-gp along the small intestine is heterogeneous, which explains why orally administered P-gp substrate drugs often show bimodal changes of plasma concentration. Secondly, we discuss the post-translational regulation of P-gp localization and function by the scaffold proteins ezrin, radixin and moesin (ERM proteins), together with recent reports indicating that tissue-specific differences in regulation by ERM proteins in normal tissues might be retained in corresponding cancerous tissues. Thirdly, we review evidence that P-gp activity is enhanced in the process of epithelial-to-mesenchymal transition (EMT), which is associated with cancer progression, without any increase in expression of P-gp mRNA. Finally, we describe two examples in which P-gp critically influences the brain distribution of drugs, i.e., oseltamivir, where low levels of P-gp associated with early development allow oseltamivir to enter the brain, potentially resulting in neuropsychiatric side effects in children, and cilnidipine, where impairment of P-gp function in ischemia allows cilnidipine to enter the ischemic brain, where it exerts a neuroprotective action.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Blood-Brain Barrier; Cell Membrane; Drug-Related Side Effects and Adverse Reactions; Epithelial-Mesenchymal Transition; Gene Expression Regulation; Humans; Intestine, Small; Pharmaceutical Preparations; Protein Processing, Post-Translational; Substrate Specificity
PubMed: 29311472
DOI: 10.1248/bpb.b17-00725 -
Journal of Veterinary Pharmacology and... Jan 2023In 2001 the molecular genetic basis of so-called "ivermectin sensitivity" in herding breed dogs was determined to be a P-glycoprotein deficiency caused by a genetic... (Review)
Review
In 2001 the molecular genetic basis of so-called "ivermectin sensitivity" in herding breed dogs was determined to be a P-glycoprotein deficiency caused by a genetic variant of the MDR1 (ABCB1) gene often called "the MDR1 mutation." We have learned a great deal about P-glycoprotein's role in drug disposition since that discovery, namely that P-glycoprotein transports many more drugs than just macrocyclic lactones that P-glycoprotein mediated drug transport is present in more places than just the blood brain barrier, that some cats have a genetic variant of MDR1 that results in P-glycoprotein deficiency, that P-glycoprotein dysfunction can occur as a result of drug-drug interactions in any dog or cat, and that the concept of P-glycoprotein "inhibitors" versus P-glycoprotein substrates is somewhat arbitrary and artificial. This paper will review these discoveries and discuss how they impact drug selection and dosing in dogs and cats with genetically mediated P-glycoprotein deficiency or P-glycoprotein dysfunction resulting from drug-drug interactions.
Topics: Dogs; Cats; Animals; Cat Diseases; Dog Diseases; ATP Binding Cassette Transporter, Subfamily B, Member 1; Ivermectin; ATP Binding Cassette Transporter, Subfamily B
PubMed: 36326478
DOI: 10.1111/jvp.13102 -
Frontiers in Bioscience (Elite Edition) Jun 2018Chemoresistance is a critical obstacle to the treatment of hepatocellular carcinoma (HCC). The mechanisms underlying resistance to doxorubicin, cisplatin, and... (Review)
Review
Chemoresistance is a critical obstacle to the treatment of hepatocellular carcinoma (HCC). The mechanisms underlying resistance to doxorubicin, cisplatin, and 5-fluorouracil involve p53 and P-glycoprotein (P-gp). p53 plays a role in cell growth; therefore, resistance mechanisms involve chemotherapy-induced apoptosis and p53 mutation and inactivation. P-gp is an energy-dependent drug efflux pump regulated by p53. Its role in drug resistance has provided new insights into the mechanisms underlying the involvement of p53 and P-gp in chemoresistance and may alter our traditional understanding of p53 and P-gp function. This review outlines the roles and principal mechanisms of p53 and P-gp mediated chemoresistance in HCC.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Antineoplastic Agents; Carcinoma, Hepatocellular; Drug Resistance, Neoplasm; Genes, p53; Humans; Liver Neoplasms
PubMed: 29772519
DOI: 10.2741/E833 -
Food and Chemical Toxicology : An... Dec 2020The drug transporter P-glycoprotein (P-gp) is often investigated in drug-interaction studies because the activity is modulated by a wide variety of xenobiotics including...
The drug transporter P-glycoprotein (P-gp) is often investigated in drug-interaction studies because the activity is modulated by a wide variety of xenobiotics including drugs, herbal products, and food components. In this study, we tested six common arylsulfonate food dyes-allura red, carmoisine, ponceau 4R, quinolone yellow, sunset yellow, and tartrazine-as activators and inhibitors of P-gp activity in vitro. The dyes were studied as P-gp activators by measuring ATPase activity in P-gp-expressing membranes. Compared to verapamil, a known activator of P-gp, the six food dyes showed no stimulatory activity. The potential for these six food dyes to act as P-gp inhibitors was tested in an intracellular efflux assay with P-gp-expressing cells. Compared to GF120918, a known P-gp inhibitor, there was no inhibitory activity for these six food dyes. The six food dyes tested do not interact with P-gp in vitro and, therefore, are unlikely cause clinical drug-food dye interactions. Further investigation is necessary to determine whether these food dyes could interact with other drug transporters.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Adenosine Triphosphatases; Biological Transport; Drug Interactions; Food Coloring Agents; Food-Drug Interactions; Humans; Verapamil
PubMed: 33011351
DOI: 10.1016/j.fct.2020.111785 -
International Journal of Molecular... Jun 2023The ABC transporter P-glycoprotein (Pgp) has been found to be involved in multidrug resistance in tumor cells. Lipids and cholesterol have a pivotal role in Pgp's...
The ABC transporter P-glycoprotein (Pgp) has been found to be involved in multidrug resistance in tumor cells. Lipids and cholesterol have a pivotal role in Pgp's conformations; however, it is often difficult to investigate it with conventional structural biology techniques. Here, we applied robust approaches coupled with cross-linking mass spectrometry (XL-MS), where the natural lipid environment remains quasi-intact. Two experimental approaches were carried out using different cross-linkers (i) on living cells, followed by membrane preparation and immunoprecipitation enrichment of Pgp, and (ii) on-bead, subsequent to membrane preparation and immunoprecipitation. Pgp-containing complexes were enriched employing extracellular monoclonal anti-Pgp antibodies on magnetic beads, followed by on-bead enzymatic digestion. The LC-MS/MS results revealed mono-links on Pgp's solvent-accessible residues, while intraprotein cross-links confirmed a complex interplay between extracellular, transmembrane, and intracellular segments of the protein, of which several have been reported to be connected to cholesterol. Harnessing the MS results and those of molecular docking, we suggest an epitope for the 15D3 cholesterol-dependent mouse monoclonal antibody. Additionally, enriched neighbors of Pgp prove the strong connection of Pgp to the cytoskeleton and other cholesterol-regulated proteins. These findings suggest that XL-MS may be utilized for protein structure and network analyses in such convoluted systems as membrane proteins.
Topics: Animals; Mice; ATP Binding Cassette Transporter, Subfamily B, Member 1; Molecular Docking Simulation; Chromatography, Liquid; Tandem Mass Spectrometry; ATP Binding Cassette Transporter, Subfamily B; Cholesterol
PubMed: 37445813
DOI: 10.3390/ijms241310627 -
Clinical Pharmacology and Therapeutics Sep 2022The role of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in drug-drug interactions (DDIs) and limiting drug absorption as well as restricting the... (Review)
Review
The role of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in drug-drug interactions (DDIs) and limiting drug absorption as well as restricting the brain penetration of drugs with certain physicochemical properties is well known. P-gp/BCRP inhibition by drugs in the gut has been reported to increase the systemic exposure to substrate drugs. A previous International Transporter Consortium (ITC) perspective discussed the feasibility of P-gp/BCRP inhibition at the blood-brain barrier and its implications. This ITC perspective elaborates and discusses specifically the hepatic and renal P-gp/BCRP (referred as systemic) inhibition of drugs and whether there is any consequence for substrate drug disposition. This perspective summarizes the clinical evidence-based recommendations regarding systemic P-gp and BCRP inhibition of drugs with a focus on biliary and active renal excretion pathways. Approaches to assess the clinical relevance of systemic P-gp and BCRP inhibition in the liver and kidneys included (i) curation of DDIs involving intravenously administered substrates or inhibitors; (ii) in vitro-to-in vivo extrapolation of P-gp-mediated DDIs at the systemic level; and (iii) curation of drugs with information available about the contribution of biliary excretion and related DDIs. Based on the totality of evidence reported to date, this perspective supports limited clinical DDI risk upon P-gp or BCRP inhibition in the liver or kidneys.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Humans; Liver; Membrane Transport Proteins; Neoplasm Proteins
PubMed: 35612761
DOI: 10.1002/cpt.2670