Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BMS-299897 is a gamma-secretase inhibitor that was effective in reducing amyloid beta-peptide (A beta) in transgenic mice and guinea pigs. Therefore, pharmacokinetic and drug metabolism studies were conducted in animals to support its clinical development. The compound appeared to have low to intermediate total body clearance and was orally bioavailable (24-100%). The oral absorption of BMS-299897 from solid dosage forms appeared to be dissolution rate-limited. BMS-299897 was distributed into extravascular space (V(ss) >or= 1.3 l kg(-1)), including brain (brain-to-plasma ratio = 0.13-0.50). BMS-299897 appeared to be a P-glycoprotein (P-gp) substrate as the brain-to-plasma ratio was two-fold higher in the mdr1a knockout mouse as compared with the wild-type. Apparent autoinduction by BMS-299897 was observed in murine and rat efficacy and toxicity studies. In vitro, BMS-299897 was a weaker inducer of cytochrome P450 3A4 (CYP3A4) and a weaker transactivator of human pregnane X receptor (hPXR) as compared with rifampicin. Induction of human UGT1A and UGT2B was evaluated in primary human hepatocytes, but the results were inconclusive. A low potential for autoinduction in humans was predicted at a clinical dose of 250 mg and the prediction was consistent with the findings from a clinical multiple-dose study with BMS-299897 in probable Alzheimer's patients.
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PMID:Studies on the pharmacokinetics and metabolism of a gamma-secretase inhibitor BMS-299897, and exploratory investigation of CYP enzyme induction. 1948 May 57

The human multidrug resistance transporter P-glycoprotein (P-gp) prevents the entry of compounds into the brain by an active efflux mechanism at the blood-brain barrier (BBB). Treatment of neurodegenerative diseases, therefore, has become a challenge and the development of new reversible inhibitors of P-gp is pertinent to overcome this problem. We report the design and synthesis of a crosslinked agent based on the Alzheimer's disease treatment galantamine (Gal-2) that inhibits P-gp-mediated efflux from cultured cells. Gal-2 was found to inhibit the efflux of the fluorescent P-gp substrate rhodamine 123 in cancer cells that over-express P-gp with an IC(50) value of approximately 0.6 microM. In addition, Gal-2 was found to inhibit the efflux of therapeutic substrates of P-gp, such as doxorubicin, daunomycin and verapamil with IC(50) values ranging from 0.3 to 1.6 microM. Through competition experiments, it was determined that Gal-2 modulates P-gp mediated efflux by competing for the substrate binding sites. These findings support a potential role of agents, such as Gal-2, as inhibitors of P-gp at the BBB to augment treatment of neurodegenerative diseases.
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PMID:Inhibition of human P-glycoprotein transport and substrate binding using a galantamine dimer. 1968 13

The efflux transporter P-glycoprotein serves as a major molecular gatekeeper at the blood-brain barrier. It has been suggested that a reduction of P-glycoprotein activity with aging might enhance exposure of brain tissue to exogenous and endogenous compounds thereby contributing to the development of neurodegenerative diseases. Brain tissue from owner-kept dogs renders an excellent tool to study the impact of aging on the background of variable environmental and genetic influencing factors. Therefore, we determined expression rates of P-glycoprotein in canine post-mortem tissue from 23 non-laboratory dogs. P-glycoprotein expression in the parahippocampal cortex exhibited a negative correlation with age. Analysis of the area labeled for P-glycoprotein in dogs aged >100 months revealed a 72% drop in P-glycoprotein expression as compared to young adults aged 23-36 months. Respective data from the dentate hilus and dentate gyrus indicated an earlier drop with a reduction by 77 and 80% in dogs aged 37-99 months in comparison with younger individuals. In contrast to the decline observed with aging in dogs without plaques, P-glycoprotein expression rates rather tended to increase with further aging in dogs with plaque formation. In conclusion, the thorough analysis of P-glycoprotein expression rates in non-laboratory dogs revealed a significant decline with aging. The data strongly support the concept that age-dependent changes might predispose to neurodegenerative diseases. In the early pathogenesis of Alzheimer's disease which is modelled by diffuse plaques in the canine brain, an up-regulation of P-glycoprotein might act as a compensatory mechanism to enhance Abeta efflux from the brain. Future studies are necessary to further evaluate the correlation between Abeta deposits and P-glycoprotein expression in different phases of the disease.
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PMID:Age-dependent decline of blood-brain barrier P-glycoprotein expression in the canine brain. 1983 57

Alzheimer's disease (AD) is the most commonly form of dementia in the elderly. The development of molecules able to detect biomarkers characteristic of AD is critical to its understanding and treatment. However, such molecules must be able to pass blood-brain barrier (BBB) which is a major impediment to the entry of many therapeutic drugs into the brain. Such a limitation applies to the development of magnetic resonance imaging molecular neuroimaging agents using biomarkers of AD-like beta-amyloid deposits, as the common extracellular contrast agents (CAs) are not able to cross an intact BBB. In this work, we have studied the ability of a series of simple Eu(3+) complexes to enter cells overexpressing or not the ABCB1 (P-gp or P-glycoprotein) protein, which is expressed at the BBB and in human embryonic astrocytes. The intracellular uptake of the Eu(3+) complexes of linear and macrocyclic polyaminocarboxylate ligands with different charges and lipophilicities was followed by atomic absorption spectrometry. Based on biochemical argument, we propose that lipophilic contrast agents can be efficiently taken up by cells and accumulate inside mitochondria when they are positively charged. The important point is that they are not P-gp substrates, which is one of the major obstacles for them to cross the BBB.
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PMID:Accumulation of Eu3+ chelates in cells expressing or not P-glycoprotein: implications for blood-brain barrier crossing. 1987 74

Multidrug resistance (MDR) mediated by overexpression of P-glycoprotein (Pgp) is one of the best characterized transporter-mediated barriers to successful chemotherapy in cancer patients and is also a rapidly emerging target in the progression of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Therefore, strategies capable of delivering chemotherapeutic agents into drug-resistant tumors and targeted radiopharmaceuticals acting as ultrasensitive molecular imaging probes for detecting functional Pgp expression in vivo could be expected to play a vital role in systemic biology as personalized medicine gains momentum in the twenty-first century. While targeted therapy could be expected to deliver optimal doses of chemotherapeutic drugs into the desired targets, the interrogation of Pgp-mediated transport activity in vivo via noninvasive imaging techniques (SPECT and PET) would be beneficial in stratification of patient populations likely to benefit from a given therapeutic treatment, thereby assisting management of drug resistance in cancer and treatment of neurodegenerative diseases. Both strategies could play a vital role in advancement of personalized treatments in cancer and neurodegenerative diseases. Via this tutorial, authors make an attempt in outlining these strategies and discuss their strengths and weaknesses.
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PMID:Targeted chemotherapy in drug-resistant tumors, noninvasive imaging of P-glycoprotein-mediated functional transport in cancer, and emerging role of Pgp in neurodegenerative diseases. 1994 24

Reduced clearance of amyloid-beta (Abeta) from brain partly underlies increased Abeta brain accumulation in Alzheimer's disease (AD). The mechanistic basis for this pathology is unknown, but recent evidence suggests a neurovascular component in AD etiology. We show here that the ATP-driven pump, P-glycoprotein, specifically mediates efflux transport of Abeta from mouse brain capillaries into the vascular space, thus identifying a critical component of the Abeta brain efflux mechanism. We demonstrate in a transgenic mouse model of AD [human amyloid precursor protein (hAPP)-overexpressing mice; Tg2576 strain] that brain capillary P-glycoprotein expression and transport activity are substantially reduced compared with wild-type control mice, suggesting a mechanism by which Abeta accumulates in the brain in AD. It is noteworthy that dosing 12-week-old, asymptomatic hAPP mice over 7 days with pregnenolone-16alpha-carbonitrile to activate the nuclear receptor pregnane X receptor restores P-glycoprotein expression and transport activity in brain capillaries and significantly reduces brain Abeta levels compared with untreated control mice. Thus, targeting intracellular signals that up-regulate blood-brain barrier P-glycoprotein in the early stages of AD has the potential to increase Abeta clearance from the brain and reduce Abeta brain accumulation. This mechanism suggests a new therapeutic strategy in AD.
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PMID:Restoring blood-brain barrier P-glycoprotein reduces brain amyloid-beta in a mouse model of Alzheimer's disease. 2010 Oct 4

The blood-brain barrier (BBB) not only impedes the influx of intravascular substances from blood to brain, but also promotes transport of substances from blood to brain or from brain to blood through several transport systems such as carrier-mediated transport, active efflux transport, and receptor-mediated transport systems. The multidrug resistance transporter P-glycoprotein (P-gp) is an ATP-dependent efflux pump and contributes to efflux of undesirable substances such as amyloid-beta:(Abeta) proteins from the brain into the blood as well as many drugs such as anti-cancer drugs. The inhibition of P-gp has favorable and unfavorable effects on living bodies. P-gp deficiency at the BBB induces the increase of Abeta:deposition in the brain of an Alzheimer disease mouse model. It is also known that the Abeta:deposition is inversely correlated with P-gp expression in the brains of elderly non-demented humans. However, the transient inhibition of P-gp by antidepressants enables medicines such as anti-cancer drugs to enter the brain. Concerning Abeta:clearance in the brain, the low-density lipoprotein receptor-related protein 1 (LRP1) is a major efflux transporter for Abeta, while the receptor for advanced glycation end products (RAGE) is a major influx transporter for Abeta:across the BBB. Dysfunction of the BBB with efflux and influx transporters may contribute to the pathogenesis of some degenerative neuronal disorders. This review will focus on several transporters and discuss how medicines pass the BBB to reach the brain parenchyma.
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PMID:Transporters in the brain endothelial barrier. 2017 45

Therapy for central nervous system (CNS) diseases requires drugs that can cross the blood-brain barrier (BBB). BBB disruption has been reported in patients with multiple sclerosis (MS) and Alzheimer's disease (AD) and the related animal models as evidenced by increased infiltration of inflammatory cells or increased staining of Igs in the central nervous system. Although CNS penetration of therapeutic agents under pathological conditions has rarely been investigated, it is commonly assumed that BBB disruption may lead to enhanced CNS penetration and also provide a "window of opportunity" through which drugs that do not normally cross BBB are able to do so. In this article, we have compared brain penetration of eight small molecules in naive animals and experimental autoimmune encephalomyelitis (EAE) mice, streptozotocin-induced mice, and TASTPM transgenic mice. The tool compounds are lipophilic transcellular drugs [GlaxoSmithKline (GSK)-A, GSK-B, GSK-C, and naproxen], lipophilic P-glycoprotein (P-gp) substrates (amprenavir and loperamide), and hydrophilic paracellular compounds (sodium fluorescein and atenolol). Our data showed that rate and extent of CNS penetration for lipophilic transcellular drugs and P-gp substrates are similar in naive and all tested animal models. The brain penetration for paracellular drugs in EAE mice is transiently increased but similar to that in naive mice at steady state. Our data suggest that, despite reported BBB disruption, CNS penetration for small molecule therapeutic agents does not increase in MS- and AD-related animal models.
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PMID:Central nervous system penetration for small molecule therapeutic agents does not increase in multiple sclerosis- and Alzheimer's disease-related animal models despite reported blood-brain barrier disruption. 2042 91

Multidrug resistance (MDR) mediated by overexpression of MDR1 (ABCB1) P-glycoprotein (Pgp) is one of the best characterized transporter-mediated barriers to successful chemotherapy in cancer patients and is also a rapidly emerging target in the progression of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Therefore, molecular imaging probes capable of imaging noninvasively Pgp and closely related transporter activities in tissues as well as tumors would be expected to contribute to personalized medicine. Interrogation of Pgp-mediated transport activity in vivo via noninvasive SPECT imaging could be beneficial for stratification of patient populations likely to benefit from a given therapeutic treatment, assist in the management of chemotherapy and aid the study of neurodegenerative diseases.
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PMID:Probing multidrug resistance P-glycoprotein transporter activity with SPECT radiopharmaceuticals. 2064 14

Multidrug efflux transporters of the ATP-Binding cassette (ABC) family, P-glycoprotein (Pgp), multidrug-resistance associated protein 4 (MRP4) and breast cancer resistance protein (BCRP), located on endothelial cells lining brain vasculature play important roles in limiting movement of substances into and enhancing their efflux from the brain. Signals from the surrounding brain normally maintain such barrier function but these may become altered in CNS pathologies such as Alzheimer's disease (AD). Previous studies have reported decreases in the glucose transporter, Glut-1, in brain vasculature of AD patients. The present study investigates the status of the multidrug efflux transporters. Sections of frozen brain from hippocampal region obtained from male AD and age-matched non-demented cases were examined for amyloid plaques and Dkk-1 expression and subjected to dual fluorescence immunochemical staining using antibodies against Pgp, BCRP or MRP4 and von Willebrand factor. Protein expression of each transporter was assessed using confocal microscopy, quantifying peak fluorescence values of cross sectional profiles across brain microvessels. Results in brain microvessels revealed expression of Pgp protein to be significantly lower in hippocampal vessels of patients with AD compared to normal individuals whereas that of MRP4 or BCRP protein was not. By contrast, analysis of the sections at protein level via Western blotting or at transcript level by qRT-PCR did not reveal significantly lower expression for either Pgp or BCRP. Such analysis did however reveal higher than normal expression in the AD brains of MRP4, probably due to gliosis, MRP4 being present also in glial cells.
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PMID:ABC efflux transporters in brain vasculature of Alzheimer's subjects. 2072 60


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