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)

The purpose of this study was to assess the effect of biorelevant apical conditions on intestinal permeability estimation in the Caco-2 system for amprenavir, a poorly water-soluble substrate of the efflux carrier P-glycoprotein (P-gp). To establish biorelevant conditions, human intestinal fluids (HIF) were aspirated from the duodenum and jejunum in fasted subjects, before and during 4 h after the intake of a standard formulation of amprenavir (Agenerase). The HIF samples were characterized with respect to the concentrations of phospholipids, individual bile salts, amprenavir, and the excipient d-alpha-tocopheryl polyethyleneglycol 1000 succinate (TPGS); subsequently, the use of these samples in the Caco-2 system during permeability estimation for amprenavir was compared to standard conditions (amprenavir 10 microM dissolved in HBSS-based transport medium). The presence of the solubilizing excipient TPGS resulted in high intraluminal amprenavir concentrations (mM-range) and affected the permeability in a concentration-dependent way. At the observed intraluminal TPGS concentrations (mM-range), TPGS appeared to completely inhibit the interaction between amprenavir and P-gp, suggesting that the effect of P-gp on transepithelial transport of amprenavir in a clinical setting is probably negligible. This study illustrates the importance of the evaluation of intraluminal conditions after drug intake and their integration in permeability estimation in vitro.
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PMID:Intraluminal drug and formulation behavior and integration in in vitro permeability estimation: a case study with amprenavir. 1637 52

D-alpha-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS 1000) is a widely used form of vitamin E. TPGS 1000 is comprised of a hydrophilic polar (water-soluble) head and a lipophilic (water-insoluble) alkyl tail. TPGS 1000 has been used as a solubilizer, an emulsifier and as a vehicle for lipid-based drug delivery formulations. Most recently, TPGS 1000 has been recognized as an effective oral absorption enhancer. An enhancing effect is consistent with a surfactant-induced inhibition of P-glycoprotein (P-gp), and perhaps other drug transporter proteins; however, the exact inhibition mechanism(s) remain unclear. Therefore, in an attempt to generate additional knowledge, we have synthesized and tested various TPGS analogs containing different PEG chain length (TPGS 200/238/400/600/1000/2000/3400/3500/4000/6000). These results demonstrate a relationship between TPGS PEG chain length and influence on rhodamine 123 (RHO) transport in Caco-2 monolayers, a relationship which may be illustrated using a Weibull distribution.
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PMID:Influence of vitamin E TPGS poly(ethylene glycol) chain length on apical efflux transporters in Caco-2 cell monolayers. 1641 30

Permeability is an underlying parameter to control drug absorption. For highly water-soluble drugs, the high correlation between their permeability and fraction absorbed in humans is reported. In the present study, to predict the absorbability of poorly water-soluble drugs in humans, a new experimental method of the permeation study was proposed and subjected to examination. Firstly, using the in vitro chamber method modified to contain 5% (final concentration) dimethyl sulufoxide (DMSO) in both compartments of the chamber (DMSO-MS), the effect of DMSO on membrane integrity was evaluated. Secondly, the correlation between the apparent permeability coefficients (Papp) obtained through DMSO-M or DMSO-MS and fractions absorbed in humans were investigated using 7 poorly water-soluble drugs. Membrane integrity of the rat intestinal tissues was maintained after using DMSO-MS, as with that after using the conventional in vitro chamber method. Papp of two paracellular markers obtained through DMSO-MS was not different from that obtained through the conventional chamber method. In the permeation study of the P-glycoprotein substrate, Papp from both mucosal to serosal and serosal to mucosal sides obtained through DMSO-MS was not significantly different from that obtained through the conventional chamber method. The correlation between Papp obtained through DMSO-MS and Fa which was expressed by the equation of Fa=1-exp (-Pappx1.38x10(5)) (r2=0.980), was more favorable than the correlation between Papp obtained through DMSO-M and Fa which was expressed by the equation of Fa=1-exp (-Pappx2.12x10(5)) (r2=0.875). These results showed that DMSO-MS was a useful method for predicting the absorbability of poorly water-soluble drugs.
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PMID:Prediction of absorbability of poorly water-soluble drugs based on permeability obtained through modified in vitro chamber method. 1641 28

Topotecan (TPT) is a semisynthetic water-soluble derivative of camptothecin (CPT) used as second-line therapy in patients with metastatic ovarian carcinoma, small cell lung cancer, and other malignancies. However, both dose-limiting toxicity and tumor resistance hinder the clinical use of TPT. The mechanisms for resistance to TPT are not fully defined, but increased efflux of the drug by multiple drug transporters including P-glycoprotein (PgP), multidrug resistance associated protein 1 (MRP1) and breast cancer resistance protein (BCRP) from tumor cells has been highly implicated. This study aimed to investigate whether overexpression of human MRP4 rendered resistance to TPT by examining the cytotoxicity profiles using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide (MTT) assay and cellular accumulation of TPT in HepG2 cells stably overexpressing MRP4. Two kinds of cell lines, HepG2 with insertion of an empty vector plasmid (V/HepG2), HepG2 cells stably expressing MRP4 (MRP4/HepG2), were exposed to TPT for 4 or 48 hr in the absence or presence of various MRP4 inhibitors including DL-buthionine-(S,R)-sulphoximine (BSO), diclofenac, celecoxib, or MK-571. The intracellular accumulation of TPT and paclitaxel (a PgP substrate) by V/HepG2 and MRP4/HepG2 cells was determined by incubation of TPT with the cells and the amounts of the drug in cells were determined by validated HPLC methods. The study demonstrated that MRP4 conferred a 12.03- and 6.86-fold resistance to TPT in the 4- and 48-hr drug-exposure MTT assay, respectively. BSO, MK-571, celecoxib, or diclofenac sensitised MRP4/HepG2 cells to TPT cytotoxicity and partially reversed MRP4-mediated resistance to TPT. In addition, the accumulation of TPT was significantly reduced in MRP4/HepG2 cells compared to V/HepG2 cells, and one-binding site model was found the best fit for the MRP4-mediated efflux of TPT, with an estimated K(m) of 1.66 microM and V(max) of 0.341 ng/min/106 cells. Preincubation of MRP4/HepG2 cells with BSO (200 microM) for 24 hr, celecoxib (50 microM), or MK-571 (100 microM) for 2 hr significantly increased the accumulation of TPT over 10 min in MRP4/HepG2 cells by 28.0%, 37.3% and 32.5% (P < 0.05), respectively. By contrast, there was no significant difference in intracellular accumulation of paclitaxel in V/HepG2 and MRP4/HepG2 cells over 120 min. MRP4 also rendered resistance to adefovir dipivoxil (bis-POM-PMEA) and methotrexate, two reported MRP4 substrates. MRP4 did not exhibit any significant resistance to other model drugs including vinblastine, vincristine, etoposide, carboplatin, cyclosporine and paclitaxel in both long (48 hr) and short (4 hr) drug-exposure MTT assays. These findings indicate that MRP4 confers resistance to TPT and TPT is the substrate for MRP4. Further studies are needed to explore the role of MRP4 in resistance to, toxicity and pharmacokinetics of TPT in cancer patients.
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PMID:Topotecan is a substrate for multidrug resistance associated protein 4. 1645 95

It is generally accepted that P-glycoprotein binds its substrates in the lipid phase of the membrane. Quantification and characterization of the lipid-transporter binding step are, however, still a matter of debate. We therefore selected 15 structurally diverse drugs and measured the binding constants from water to the activating (inhibitory) binding region of P-glycoprotein, K(tw(1)) (K(tw(2))), as well as the lipid-water partition coefficients, K(lw). The former were obtained by measuring the concentrations of half-maximum activation (inhibition), K(1) (K(2)), in living NIH-MDR-G185 mouse embryo fibroblasts using a Cytosensor microphysiometer, and the latter were derived from surface activity measurements. This allowed determination of the membrane concentration of drugs at half-maximum P-glycoprotein activation (C(b(1)) = (0.02 to 67) mmol/L lipid), which is much higher than the corresponding aqueous concentration (K(1) = (0.02 to 376) microM). Moreover we determined the free energy of drug binding from water to the activating binding region of the transporter (DeltaG degrees (tw(1)) = (-30 to -54) kJ/mol), the free energy of drug partitioning into the lipid membrane (DeltaG degrees (lw) = (-23 to -34) kJ/mol), and, as the difference of the two, the free energy of drug binding from the lipid membrane to the activating binding region of the transporter (DeltaG degrees (tl(1)) = (-7 to -27) kJ/mol). For the compounds tested DeltaG degrees (tl(1)) was less negative than DeltaG degrees (lw) but varied more strongly. The free energies of substrate binding to the transporter within the lipid phase, DeltaG degrees (tl(1)), are consistent with a modular binding concept, where the energetically most efficient binding module comprises two hydrogen bond acceptor groups.
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PMID:Quantification and characterization of P-glycoprotein-substrate interactions. 1650 57

In the pharmaceutical industry, orally active compounds are required to have sufficient water solubility to enable dissolution within the gastrointestinal tract prior to absorption. Limited dissolution within the gastrointestinal tract often reduces the bioavailability of hydrophobic drugs. To improve gastrointestinal tract dissolution, nonaqueous solvents are often used in the form of emulsions and microemulsions. Here, we show that oil-free polyelectrolyte nanosystems (micellar dispersions and 100-300 nm particles) prepared from poly(ethylenimines) derivatized with cetyl chains and quaternary ammonium groups are able to encapsulate high levels of hydrophobic drug (0.20 g of drug per g of polymer) for over 9 months, as demonstrated using cyclosporine A (log P = 4.3). The polyelectrolytes facilitate the absorption of hydrophobic drugs within the gastrointestinal tract by promoting drug dissolution and by a hypothesized mechanism involving paracellular drug transport. Polyelectrolyte nanoparticle drug blood levels are similar to those obtained with commercial microemulsion formulations. The polyelectrolytes do not promote absorption by inhibition of the P-glycoprotein efflux pump.
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PMID:Polyelectrolyte nanoparticles with high drug loading enhance the oral uptake of hydrophobic compounds. 1667 33

It is now well recognized that membrane efflux transporters, especially P-glycoprotein (P-gp; ABCB1), play a role in determining the absorption, distribution, metabolism, excretion, and toxicology behaviors of some drugs and molecules in development. An investment in screening structure-activity relationship (SAR) is warranted in early discovery when exposure and/or target activity in an in vivo efficacy model is not achieved and P-gp efflux is identified as a rate-limiting factor. However, the amount of investment in SAR must be placed into perspective by assessing the risks associated with the intended therapeutic target, the potency and margin of safety of the compound, the intended patient population(s), and the market competition. The task of rationally designing a chemistry strategy for circumventing a limiting P-gp interaction can be daunting. The necessity of retaining biological potency and metabolic stability places restrictions on what can be done, and the factors for P-gp recognition of substrates are complicated and poorly understood. The parameters within the assays that affect overall pump efficiency or net efflux, such as passive diffusion, membrane partitioning, and molecular interaction between pump and substrate, should be understood when interpreting data sets associated with chemistry around a scaffold. No single, functional group alone is often the cause, but one group can accentuate the recognition points existing within a scaffold. This can be likened to a rheostat, rather than an on/off switch, where addition or removal of a key group can increase or decrease the pumping efficiency. The most practical approach to de-emphasize the limiting effects of P-gp on a particular scaffold is to increase passive diffusion. Efflux pumping efficiency may be overcome when passive diffusion is fast enough. Eliminating, or substituting with fewer, groups that solvate in water, or decreasing their hydrogen bonding capacity, and adding halogen groups can increase passive diffusion. Reducing molecular size, replacing electronegative atoms, blocking or masking H-bond donors with N-alkylation or bulky flanking groups, introducing constrained conformation, or by promoting intramolecular hydrogen bonds are all examples of steps to take. This review discusses our understanding of how P-gp recognizes and pumps compounds as substrates and describes cases where structural changes were made in a chemical scaffold to circumvent the effects of P-gp interactions.
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PMID:P-glycoprotein recognition of substrates and circumvention through rational drug design. 1668 64

Digoxin, a substrate of P-glycoprotein (Pgp) and cytochrome P450 3a (Cyp3a), was used to illustrate the inductive effects of pregnenolone-16alpha-carbonitrile (PCN), a ligand of the pregnane X receptor, on the absorption and disposition of [3H]digoxin in the vascularly perfused rat small intestine preparation. Although increased Cyp3a protein was observed with Western blotting analysis after PCN treatment, metabolism of digoxin to the digoxigenin bis-digitoxoside metabolite in the rat small intestine remained insignificant (<4% dose). PCN pretreatment significantly decreased blood perfusate [3H]digoxin concentrations for both systemic and intraluminal administrations of [3H]digoxin due to increased Pgp levels. The apical secretion by Pgp increased at 90 min with PCN treatment, from 11.2 +/- 5.1% of dose to 20.1 +/- 8.6% of dose after systemic administration of [3H]digoxin; this increase was, however, statistically insignificant (P = 0.13) because of the high variability among preparations. When the composite data for the control and PCN-treated preparations were fit to published physiologically based pharmacokinetic models: the traditional model and the segregated flow model, suboptimal parameters were obtained. The data were further fit to expanded models with a bilayer membrane compartment housing the Pgp adjacent to the apical membrane, or an unstirred water layer (UWL) external to the apical membrane. The models with the UWL yielded improved fits and reasonable parameters associated with digoxin absorption, suggesting that the UWL posed as a barrier for digoxin absorption. Similar results were obtained with the segmental models (the segmental traditional model and the segmental segregated flow model) using the UWL, when heterogeneous distributions of Pgp in the duodenum, jejunum, and ileum were considered.
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PMID:P-glycoprotein and an unstirred water layer barring digoxin absorption in the vascularly perfused rat small intestine preparation: induction studies with pregnenolone-16alpha-carbonitrile. 1675 Dec 64

In children, the therapeutic benefits and potential risks associated with drug treatment may be different from those in adults and will depend on the exposure, receptor sensitivity and relationship between effect and exposure. In this paper, key factors undergoing maturational changes accounting for differences in drug metabolism and disposition in the paediatric population compared with adults are reviewed. Gastric and duodenal pH, gastric emptying time, intestinal transit time, secretion and activity of bile and pancreatic fluid, bacterial colonisation and transporters, such as P-glycoprotein (P-gp), are important factors for drug absorption, whereas key factors explaining differences in drug distribution between the paediatric population and adults are organ size, membrane permeability, plasma protein concentration and characteristics, endogenous substances in plasma, total body and extracellular water, fat content, regional blood flow and transporters such as P-gp, which is present not only in the gut, but also in liver, kidney, brain and other tissues. As far as drug metabolism is concerned, important differences have been found in the paediatric population compared with adults both for phase I enzymes (oxidative [e.g., cytochrome P450 (CYP)1A2, and CYP3A7 versus -3A4], reductive and hydrolytic enzymes) and phase II enzymes (e.g., N-methyltransferases and glucuronosyltransferases). Generally, the major enzyme differences observed in comparison with the adult age are in newborn infants, although for some enzymes (e.g., glucuronosyltransferases and other phase II enzymes) important differences still exist between infants and toddlers and adults. Finally, key factors undergoing maturational changes accounting for differences in renal excretion in the paediatric population compared with adults are glomerular filtration and tubular secretion. The ranking of the key factors varies according to the chemical structure and physicochemical properties of the drug examined, as well as to the characteristics of its formulation. It would be important to generate additional information on the developmental aspects of renal P-gp and of other renal transporters, as has been done and is still being done with the different -isozymes involved in drug metabolism.
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PMID:Differences in absorption, distribution, metabolism and excretion of xenobiotics between the paediatric and adult populations. 1686 55

GW844520 is a potent and selective inhibitor of the cytochrome bc1 complex of mitochondrial electron transport in P. falciparum, the parasite primarily responsible for the mortality associated with malaria worldwide. GW844520 is fully active against the parasite including resistance isolates, showing no cross resistance with agents in use. To evaluate full potential of this development candidate, we conducted drug metabolism and pharmacokinetic studies of this novel anti-malarial. GW844520 had low blood clearance of about 0.5-4% of hepatic blood flow and a steady-state volume of distribution of 2-4 times total body water in mouse, rat, dog, and monkey. Oral bioavailability was high (51-100%). Consistent with the in vivo data, GW844520 had low intrinsic clearance in liver microsomes and hepatocytes of animal and human origin, high passive cellular permeability and was not a P-glycoprotein substrate. GW844520 did not associate appreciably with blood cells but was highly bound to plasma proteins (>99%) in all species. GW844520 was a substrate and inhibitor of human CYP2D6 but not of CYP1A2, 2C9, 2C19, and 3A4. This conjunctive analysis supports continued evaluation of this compound in definitive pre-IND studies and exemplifies our strategy supporting the discovery of novel agents to treat diseases of the developing world.
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PMID:Preclinical drug metabolism and pharmacokinetic evaluation of GW844520, a novel anti-malarial mitochondrial electron transport inhibitor. 1689 5


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