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

---

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

Quercetin was reported to modulate CYP isoenzymes and P-glycoprotein (Pgp), a drug efflux transporter. Our previous study reported that quercetin significantly decreased the bioavailability of cyclosporin, a substrate for CYP3A4 and Pgp, in rats and pigs. Ginkgo and onion contain quercetin and its glycosides as St. John's Wort. The coadministration of cyclosporin with ginkgo or onion may be subject to clinically relevant interactions as St. John's Wort. Therefore, this study aimed to investigate the influences of ginkgo and onion on the absorption and disposition of cyclosporin in rats. Cyclosporin was administered orally and intravenously to rats with and without an oral dose of ginkgo or onion in crossover designs. Blood samples were collected via cardiopuncture and blood cyclosporin concentration was assayed by a specific monoclonal fluorescence polarization immunoassay. Everted gut sac was used to investigate the effects of ginkgo and onion on the function of intestinal Pgp. Oral coadministration of ginkgo and onion significantly decreased the Cmax of cyclosporin by 62% and 60%, and reduced the AUC0-t by 51% and 68%, respectively, whereas no influence was observed when cyclosporin was given intravenously. This indicates that the interactions between cyclosporin and ginkgo or onion occurred mainly at the absorption site. In conclusion, ginkgo and onion markedly decreased the oral bioavailability of cyclosporin. We suggest that concurrent intake of quercetin-rich herbs or foods with cyclosporin are better avoided in order to ensure the efficacy of cyclosporin.
...
PMID:Marked decrease of cyclosporin bioavailability caused by coadministration of ginkgo and onion in rats. 1676 74

There is marked interindividual variability in trough blood levels of tacrolimus (TRL) following standard dosing. TRL is a substrate for P-glycoprotein (P-gp), the product of the multidrug resistance-1 (MDR1)(ABCB1) gene. P-gp acts as a membrane efflux pump, which affects TRL absorption from the gut. Some of the single nucleotide polymorphisms (SNP) of ABCB1 gene are associated with pharmacokinetic characteristics of TRL. The objective of this study was to determine the role of ABCB1 C3435T polymorphism on TRL dose requirements, trough values and dose-adjusted trough TRL concentrations among Turkish renal transplant recipients. Renal transplant recipients receiving TRL (n=92) were genotyped for ABCB1. TRL daily doses, trough concentrations, dose-adjusted trough concentrations, demographic features, and clinical data were obtained at 1, 6, and 12 months after renal transplantation. The frequency of the ABCB1 3435 CC genotype was 30.4%, whereas 47.8% of patients were 3435 CT and 21.7% of patients were 3435 TT. TRL daily doses were significantly lower among patients with the 3435 TT genotype at months 1 and 6. At 6 and 12 months after transplantation patients who were homozygous for the ABCB1 3435 CC showed significantly lower dose-adjusted trough TRL concentrations compared with subjects of 3435 TT and CT genotypes. Knowledge of ABCB1 genotype may be useful to adjust the optimal dose of TRL in transplant patients, thereby rapidly achieving target concentrations.
...
PMID:The effect of MDR1 (ABCB1) polymorphism on the pharmacokinetic of tacrolimus in Turkish renal transplant recipients. 1679 84

The interaction between drug-metabolising enzymes and active transporters is an emerging concept in pharmacokinetics. In the gut mucosa, P-glycoprotein and cytochrome P450 (CYP)3A functionally interact in three ways: i) drugs are repeatedly taken up and pumped out of the enterocytes by P-glycoprotein, thus increasing the probability of drugs being metabolised; ii) P-glycoprotein keeps intracellular drug concentrations within the linear range of the metabolising capacity of CYP3A; and iii) P-glycoprotein transports drug metabolites formed in the mucosa back into the gut lumen. In comparison with the gut mucosa, in hepatocytes the spatial sequence of CYP3A and P-glycoprotein is reversed, resulting in different effects when the activity of one or both are changed. CYP3A and P-glycoprotein are both regulated by nuclear receptors such as the pregnane X receptor (PXR). There is significant genetic variability of CYP3A, P-glycoprotein and PXR and their expression and activity is dependent on coadministered drugs, herbs, food, age, hormonal status and disease. Future pharmacogenomic and pharmacokinetic studies will have to take all three components into account to allow for valid conclusions.
...
PMID:Functional interactions between P-glycoprotein and CYP3A in drug metabolism. 1686 30

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.
...
PMID:Differences in absorption, distribution, metabolism and excretion of xenobiotics between the paediatric and adult populations. 1686 55

P-glycoprotein (P-gp) the multidrug transporter is a well-characterised member of the super-family of ATP-binding cassette (ABC) transporters, and mediates the clearance of xenotoxins against steep concentration gradients at the expense of ATP hydrolysis. The primary function of this protein is to prevent the uptake of toxic compounds from the gut into the body, and to protect vital structures such as the brain, cerebrospinal fluid, testis, foetus and bone marrow against toxins. Although P-gp transports a wide range of compounds, which is advantageous, it can also be a disadvantage and may interfere with the delivery of drugs to target tissues resulting in multidrug resistance. In the present review: (i) we consider our current understanding of the structure of P-glycoprotein, (ii) discuss substrate binding and its coupling to ATPase activity, (iii) provide insight into key features which define P-glycoprotein substrates/inhibitors and the ability to predict potential substrates in silico, (iv) provide an overview of existing models of pump function and (v) present emerging concepts into the regulation of P-glycoprotein expression, with particular reference to multidrug resistance.
...
PMID:A primer on the mechanics of P-glycoprotein the multidrug transporter. 1709 41

Chronic renal failure (CRF) is associated with an increased bioavailability of drugs by a poorly understood mechanism. One hypothesis is a reduction in the elimination of drugs by the intestine, i.e., drug elimination mediated by protein membrane transporters such as P-glycoprotein (Pgp) and multidrug-resistance-related protein (MRP) 2. The present study aimed to investigate the repercussions of CRF on intestinal transporters involved in drug absorption [organic anion-transportingpolypeptide (Oatp)] and those implicated in drug extrusion (Pgp and MRP2). Pgp, MRP2, MRP3, Oatp2, and Oatp3 protein expression and Pgp, MRP2, and Oatp3 mRNA expression were assessed in the intestine of CRF (induced by five-sixth nephrectomy) and control rats. Pgp and MRP2 activities were measured using the everted gut technique. Rat enterocytes and Caco-2 cells were incubated with sera from control and CRF rats to characterize the mechanism of transporters' down-regulation. Protein expression of Pgp, MRP2, and MRP3 were reduced by more than 40% (p < 0.01) in CRF rats, whereas Oatp2 and Oatp3 expression remained unchanged. There was no difference in the mRNA levels assessed by real-time polymerase chain reaction. Pgp and MRP2 activities were decreased by 30 and 25%, respectively, in CRF rats compared with control (p < 0.05). Uremic sera induced a reduction in protein expression and in activity of drug transporters compared with control sera. Our results demonstrate that CRF in rats is associated with a decrease in intestinal Pgp and MRP2 protein expression and function secondarily to serum uremic factors. This reduction could explain the increased bioavailability of drugs in CRF.
...
PMID:Down-regulation of intestinal drug transporters in chronic renal failure in rats. 1713 44

P-glycoprotein (Pgp; ABCB1), a member of the ATP-binding cassette (ABC) superfamily, exports structurally diverse hydrophobic compounds from the cell, driven by ATP hydrolysis. Pgp expression has been linked to the efflux of chemotherapeutic drugs in human cancers, leading to multidrug resistance (MDR). The protein also plays an important physiological role in limiting drug uptake in the gut and entry into the brain. Substrates partition into the lipid bilayer before interacting with Pgp, which has been proposed to function as a hydrophobic vacuum cleaner. Low- and medium-resolution structural models of Pgp suggest that the 2 nucleotide-binding domains are closely associated to form a nucleotide sandwich dimer. Pgp is an outwardly directed flippase for fluorescent phospholipid and glycosphingolipid derivatives, which suggests that it may also translocate drug molecules from the inner to the outer membrane leaflet. The ATPase catalytic cycle of the protein is thought to proceed via an alternating site mechanism, although the details are not understood. The lipid bilayer plays an important role in Pgp function, and may regulate both the binding and transport of drugs. This review focuses on the structure and function of Pgp, and highlights the importance of fluorescence spectroscopic techniques in exploring the molecular details of this enigmatic transporter.
...
PMID:Shedding light on drug transport: structure and function of the P-glycoprotein multidrug transporter (ABCB1). 1721 84

Over a million new cases of cancers are diagnosed each year in the United States and over half of these patients die from these devastating diseases. Thus, cancers cause a major public health problem in the United States and worldwide. Chemotherapy remains the principal mode to treat many metastatic cancers. However, occurrence of cellular multidrug resistance (MDR) prevents efficient killing of cancer cells, leading to chemotherapeutic treatment failure. Numerous mechanisms of MDR exist in cancer cells, such as intrinsic or acquired MDR. Overexpression of ATP-binding cassette (ABC) drug transporters, such as P-glycoprotein (P-gp or ABCB1), breast cancer resistance protein (BCRP or ABCG2) and/or multidrug resistance-associated protein (MRP1 or ABCC1), confers an acquired MDR due to their capabilities of transporting a broad range of chemically diverse anticancer drugs. In addition to their roles in MDR, there is substantial evidence suggesting that these drug transporters have functions in tissue defense. Basically, these drug transporters are expressed in tissues important for absorption, such as in lung and gut, and for metabolism and elimination, such as in liver and kidney. In addition, these drug transporters play an important role in maintaining the barrier function of many tissues including blood-brain barrier, blood-cerebral spinal fluid barrier, blood-testis barrier and the maternal-fetal barrier. Thus, these ATP-dependent drug transporters play an important role in the absorption, disposition and elimination of the structurally diverse array of the endobiotics and xenobiotics. In this review, the molecular mechanism of ATP-dependent solute transport by MRP1 will be addressed.
...
PMID:A molecular understanding of ATP-dependent solute transport by multidrug resistance-associated protein MRP1. 1729 59

The extracts from the roots of Salvia miltiorrhiza Bunge (Danshen) are widely and traditionally used in the treatment of angina pectoris, acute myocardial infarct, hyperlipidemia and stroke in China and other Asian countries. In this study, we have investigated the role of P-glycoprotein (P-gp) in the intestinal absorption of tanshinone IIA (TSA), a major active constituent of Danshen, using several in vitro and in vivo models. The oral bioavailability of TSA was about 2.9-3.4% in rats, with non-linear pharmacokinetics when its dosage increased. In a single pass rat intestinal perfusion model, the permeability coefficients (P(app)) based on TSA disappearance from the luminal perfusates (P(lumen)) were 6.2- to 7.2-fold higher (P < 0.01) than those based on drug appearance in mesenteric venous blood (P(blood)). The P(blood), but not P(lumen), was significantly increased when co-perfused with verapamil, or quinidine (both P-gp inhibitors). The uptake and efflux of TSA in confluent Caco-2 cells were significantly altered in the presence of verapamil, quinidine, MK-571, or probenecid. The transport of TSA across Caco-2 monolayers was pH-, temperature- and ATP-dependent. Furthermore, the transport from the apical (AP) to basolateral (BL) side of the Caco-2 monolayers was 3.3- to 8.5-fold lower than that from the BL to AP side, but such a polarized transport was attenuated by co-incubated verapamil or quinidine. A polarized transport was also observed in the control MDCKII cells and more apparent in MDR1-MDCKII monolayers, with the P(app) values of TSA in the BL-AP direction being 7- to 9-fold higher in MDR1-MDCKII monolayers than those in the control MDCKII cells. Moreover, TSA significantly inhibited P-gp-mediated transport of digoxin in P-gp-overexpressing membrane vesicles with an IC(50) of 2.6 microM, but stimulated vanadate-sensitive P-gp ATPase activity with estimated K(m) and V(max) values of 10.70 +/- 0.69 microM and 67.65 +/- 1.31 nmol/min/mg protein, respectively. TSA was extensively metabolized to tanshinone IIB (TSB), and two other oxidative metabolites in rat liver microsomes, but the formation rate of TSB in rat intestinal microsomes was only about 1/10 of that in liver microsomes. These findings indicate that TSA is a substrate and reversing agent for P-gp; and P-gp-mediated efflux of TSA into the gut lumen and the first-pass metabolism contribute to the low oral bioavailability. Further studies are needed to explore the role of other drug transporters and first-pass metabolism in the low bioavailability of TSA.
...
PMID:Role of P-glycoprotein in the intestinal absorption of tanshinone IIA, a major active ingredient in the root of Salvia miltiorrhiza Bunge. 1750 22

Cytochrome P450 (CYP) 3A4 is the most abundant enzyme of CYPs in the liver and gut that metabolizes approximately 50% currently available drugs. A number of important drugs have been identified as substrates, inducers, and/or inhibitors of CYP3A4. The substrates of CYP3A4 considerably overlap with those of P-glycoprotein. Both CYP3A4 and P-glycoprotein are subject to inhibition and induction by a number of factors. Mechanism-based inhibition of CYP3A4 is characterized by NADPH-, time-, and concentration-dependent enzyme inactivation occurring when some xenobiotics or drugs are converted by CYPs to reactive metabolites. Such an inhibition of CYP3A4 is caused by chemical modification of the heme, the protein, or both as a result of covalent binding of modified heme to the protein. To date, the identified clinically important mechanism-based CYP3A4 inhibitors mainly include macrolide antibiotics (eg, clarithromycin and erythromycin), anti-HIV agents (eg, ritonavir and delavirdine), antidepressants (eg, fluoxetine and fluvoxamine), calcium channel blockers (eg, verapamil and diltiazem), steroids and their modulators (eg, gestodene and mifepristone), and several herbal and dietary components. The inactivation of CYP3A4 by drugs often causes unfavorable and long-lasting drug-drug interactions and probably fatal toxicity, depending on many factors associated with the enzyme, drugs, and the patients. Clinicians are encouraged to have a sound knowledge of drug-induced, mechanism-based CYP3A4 inhibition; take proper cautions, and perform close monitoring for possible drug interactions when using drugs that are mechanism-based CYP3A4 inhibitors. To minimize drug-drug interactions involving mechanism-based CYP3A4 inhibition, it is necessary to choose safe drug combination regimens, adjust drug dosages appropriately, and conduct therapeutic drug monitoring for drugs with narrow therapeutic indices.
...
PMID:Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. 1804 68


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---