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)

Until recently, the blood-brain barrier was viewed as a static lipid membrane barrier. Physical attributes of the cerebral endothelial cells such as the presence of tight junctions, paucity of vesicles or caveolae, and high electrical resistance were believed to be the primary components that provide the membrane selectivity of the blood-brain barrier to a variety of circulating compounds from the periphery. However, results from molecular biology, immunocytochemistry, biochemistry, and transport studies show that the cerebral endothelial cells possess an asymmetrical array of metabolic enzymes (i.e., alkaline phosphatase, cytochrome P450 enzymes, glutathione transferases) and energy-dependent efflux transport proteins (i.e., P-glycoprotein and Multidrug-resistance proteins) that are instrumental to the barrier function. P-glycoprotein, a membrane-associated, energy-dependent, efflux transporter, is expressed in brain parenchyma (i.e., astrocytes and microglia) as well as in blood-brain and blood-cerebrospinal fluid barriers. Its function along the blood-brain barrier is believed to prevent the accumulation of potentially harmful compounds in the brain by actively removing them from the brain into the peripheral circulation. This is a brief review on the expression and activity of P-glycoprotein at the blood-brain barrier, which reports on the localization of the protein in rat brain capillaries in situ as well as in a well-characterized in vitro model of the blood-brain barrier, an immortalized rat brain endothelial cell line, the RBE4. Immunocytochemical analysis employing various P-glycoprotein monoclonal antibodies, demonstrated the presence of the protein along the plasma membrane, in plasmalemmal vesicles and nuclear envelope of rat cerebral endothelial cells, both in situ and in vitro. Western blot analysis revealed a single band with a molecular weight of 170-180 kDa, a size previously reported for P-glycoprotein, in RBE4 cells. In addition, results from functional studies show that the accumulation of the P-glycoprotein substrate digoxin by RBE4 monolayer cells is significantly enhanced in the presence of standard P-glycoprotein inhibitors (verapamil, cyclosporin A, PSC 833), protease inhibitors (saquinavir, ritonavir, indinavir), and the metabolic inhibitor, sodium azide. These results demonstrate the functional expression of P-glycoprotein in the immortalized rat brain endothelial cell line, RBE4. Novel in situ and in vitro intracellular locations of P-glycoprotein in cerebral endothelial cells have been identified suggesting that this transporter may play a significant role in the subcellular distribution of substrates in the brain.
...
PMID:Functional expression and localization of P-glycoprotein at the blood brain barrier. 1211 43

Numerous cytochrome P450 inhibitors have been described as effective modulators of cytochrome P450 isoforms activity in vitro. Their inhibitory efficiency may be considerably modified after in vivo application. The aim of this study was to examine the effect of oral administration of diallyl sulfide--a cytochrome P450 2E1 inhibitor and cimetidine--a cytochrome P450 2C6 and 2C11 inhibitor on rat serum concentration of phenacetin and its metabolite acetaminophen. Both inhibitors increased area under the curve (AUC(0-4 h)) for phenacetin by 50%. Only cimetidine reduced AUC(0-4 h) for acetaminophen indicating inhibition of O-deethylation activity. Quinidine--a cytochrome P450 2D subfamily and P-glycoprotein inhibitor did not change significantly phenacetin bioavailability. These results suggest that diallyl sulfide inhibits the deacetylation pathway catalysed by arylamine N-acetyl transferase. Beside cytochrome P450 1A2 other cytochrome P450 isoforms (2A6 and/or 2C11) are involved in phenacetin O-deethylation in rat.
...
PMID:In vivo effect of diallyl sulfide and cimetidine on phenacetin metabolism and bioavailability in rat. 1213 47

1. The use of herbal products to treat a wide range of conditions is rising rapidly, leading to increased intake of phytochemicals. Recent studies revealed potentially fatal interactions between herbal remedies and traditional drugs. 2. In transplant patients, self-medication with St John's wort (Hypericum perforatum) has led to a drop in plasma levels of the immunosuppressant drug cyclosporine, causing tissue rejection. 3. Intake of St John's wort increases the expression of intestinal P-glycoprotein and the expression of CYP3A4 in the liver and intestine. The combined up-regulation in intestinal P-glycoprotein and hepatic and intestinal CYP3A4 impairs the absorption and stimulates the metabolism of cyclosporine, leading to subtherapeutic plasma levels. The St John's wort component, hyperforin, contributes to the induction of CYP3A4. 4. St John's wort also enhances the metabolism of other CYP3A4 substrates including the protease inhibitors indinavir and nevirapine, oral contraceptives, and tricyclic antidepressants such as amitriptyline. 5. Other herbal remedies with the potential to modulate cytochrome P450 activity and thus participate in interactions with conventional drugs include Milk thistle, Angelica dahurica, ginseng, garlic preparations, Danshen and liquorice. 6. Herbal products are currently not subject to the rigorous testing indispensable for conventional drugs. However, if potential drug interactions are to be predicted, it is essential that the ability of herbal products to interfere with drug-metabolizing enzyme systems is fully established.
...
PMID:Pharmacokinetic interactions between herbal remedies and medicinal drugs. 1216 Apr 80

The clinical management of tacrolimus, a macrolide used as immunosuppressant after transplantation, is complicated by its narrow therapeutic index in combination with inter- and intraindividually variable pharmacokinetics. As a substrate of cytochrome P450 (CYP) 3A enzymes and P-glycoprotein, tacrolimus interacts with several other drugs used in transplantation medicine, which also are known CYP3A and/or P-glycoprotein inhibitors and/or inducers. In clinical studies, CYP3A/P-glycoprotein inhibitors and inducers primarily affect oral bioavailability of tacrolimus rather than its clearance, indicating a key role of intestinal P-glycoprotein and CYP3A. There is an almost complete overlap between the reported clinical drug interactions of tacrolimus and those of cyclosporin. However, in comparison with cyclosporin, only few controlled drug interaction studies have been carried out, but tacrolimus drug interactions have been extensively studied in vitro. These results are inconsistent and are of poor predictive value for clinical drug interactions because of false negative results. P-glycoprotein regulates distribution of tacrolimus through the blood-brain barrier into the brain as well as distribution into lymphocytes. Interaction of other drugs with P-glycoprotein may change tacrolimus tissue distribution and modify its toxicity and immunosuppressive activity. There is evidence that ethnic and gender differences exist for tacrolimus drug interactions. Therapeutic drug monitoring to guide dosage adjustments of tacrolimus is an efficient tool to manage drug interactions. In the near future, progress can be expected from studies evaluating potential pharmacokinetic interactions caused by herbal preparations and food components, the exact biochemical mechanism underlying tacrolimus toxicity, and the potential of inhibition of CYP3A and P-glycoprotein to improve oral bioavailability and to decrease intraindividual variability of tacrolimus pharmacokinetics.
...
PMID:Mechanisms of clinically relevant drug interactions associated with tacrolimus. 1219 Mar 31

The contributions of cytochrome P450 3A (CYP3A) and P-glycoprotein to sirolimus oral bioavailability in rats were evaluated by coadministration of sirolimus (Rapamune) with the CYP3A inhibitor ketoconazole or the P-glycoprotein inhibitor D-alpha-tocopheryl poly(ethylene glycol 1000) succinate (TPGS). Groups of six male Sprague-Dawley rats (250-300 g) were administered Rapamune (1 mg/kg) by oral gavage, alone and with ketoconazole (30 mg/kg) or TPGS (50 mg/kg). Sirolimus levels were measured in whole blood over a 6-h time course. Sirolimus C(max) (6.6 +/- 1.6 versus 26 +/- 7 ng/ml) and area under the concentration versus time curve from 0 to 6 h (AUC(0-6)) (22 +/- 7 versus 105 +/- 27 ng. h/ml) were increased 3- to 5-fold by ketoconazole. Median T(max) (1.5-2 h) was unchanged. TPGS had no effect on sirolimus absorption. The interaction of sirolimus with P-glycoprotein was also evaluated in vitro using HCT-8 and Caco-2 cell monolayers. Consistent with published reports, sirolimus was a good inhibitor of P-glycoprotein, inhibiting polarized basolateral-to-apical flux of rhodamine 123 with an IC(50) of 0.625 to 1.25 microM (cyclosporine caused >80% inhibition at 5 microM). Sirolimus did not demonstrate significant polarized flux in either direction using the same monolayers (basolateral-to-apical flux was <2 times the apical-to-basolateral). Moreover, sirolimus flux was not impacted by cyclosporine, suggesting that it does not undergo P-glycoprotein-mediated transport in this system. The lack of significant sirolimus transport by P-glycoprotein may, in part, explain the lack of a TPGS effect on sirolimus absorption in rats.
...
PMID:Sirolimus oral absorption in rats is increased by ketoconazole but is not affected by D-alpha-tocopheryl poly(ethylene glycol 1000) succinate. 1223 65

Many clinically important drug interactions occur due to inhibition of human liver cytochrome P450 3A (CYP3A) metabolism. The drug efflux pump P-glycoprotein (Pgp) can be an additional locus contributing to these drug interactions because there is overlap in drugs that are substrates for both proteins. We screened a number of CYP3A inhibitors (macrolide antibiotics, azole antifungals, and ergotpeptides) for their ability to interact with Pgp, compared with prototypical Pgp inhibitors. We used cell lines expressing human, mouse, and rat mdr1 genes. Pgp antagonism was defined by interactions of the drugs with four cell lines (LLC-PK1, L-MDR1, L-mdr1a, and L-mdr1b) using a microfluorometric calcein-AM assay and characterized for their inhibitor constant (K(i)) toward calcein-AM. The compounds were further defined for their ability to inhibit MDR1 by their effect on vinblastine accumulation into L-MDR1 cells. Representative compounds from each class of drugs were further tested as Pgp substrates, defined by the ability of human Pgp or mouse mdr1a/Pgp to transport them across a polarized kidney epithelial cell in vitro. These same compounds were administered radiolabeled in vivo to mdr1a (+/+) and (-/-) mice and the distribution of radioactivity compared. The results are summarized as follows: 1) Some drug interactions with Pgp were substrate- and/or assay-dependent. 2) Ergot alkaloids were identified as a class of MDR1/Pgp chemosensitizers. 3) The Ergot alkaloids revealed species differences in the structure-activity relationships for inhibition of Pgp. Simultaneous inhibition of Pgp by many CYP3A inhibitors contributes to human variation in the extent of drug-drug interactions.
...
PMID:Interaction of cytochrome P450 3A inhibitors with P-glycoprotein. 1223 67

There are pharmacological differences between women and men that have important clinical consequences. For several drugs, there is a higher incidence in women of drug-induced QT prolongation and a potentially fatal arrhythmia, torsades de pointes. This may be a reflection of the longer baseline QT interval in women. A difference in cardiovascular disease between women and men is that women have a higher mortality rate after myocardial infarction (MI). Women also have a higher rate of hemorrhagic stroke after receiving thrombolytic therapy for an MI. Differences in effectiveness of analgesics have been demonstrated, with kappa opioids providing pain relief for women but not men. Drugs may have different pharmacokinetics in women and men because of differences in phase I and phase II enzymes that metabolize drugs. Conflicting results about biological sex differences have been reported for the major drug metabolizing enzyme, cytochrome P450 3A4 (3A4) and may be related to a role for P-glycoprotein, a cell membrane transporter, reported as two times higher in male livers than those of females. It has been reported that boys need a higher dose of 6-mercaptopurine, which is metabolized by thiopurine methyltransferase (TPMT). TPMT is reported to be 14% higher in male human liver biopsies than those from females. Verapamil, a drug for angina and hypertension, has different clearance and side effects in men and women. Ethnic/racial variations have also been demonstrated with the drug metabolizing enzymes, CYP2C9, 2C19, and 2D6.
...
PMID:Biologic and molecular mechanisms for sex differences in pharmacokinetics, pharmacodynamics, and pharmacogenetics: Part I. 1239 93

The use of herbal medications and other alternative therapies is accelerating. Survey data clearly indicate that these agents are frequently combined with prescription and over-the-counter medications. The herbal antidepressant St. John's wort (Hypericum perforatum) is one of the most commonly utilized herbal agents. In spite of growing concern and examples of herb-drug interactions, little systematic research has been published or funded in this area. Computerized searches of the biomedical literature were undertaken utilizing MEDLINE, Current Contents, and PsycINFO computer databases (years 1966-December 2000) and by review of bibliographies to identify all pertinent case reports, case series, and formal studies for this review using search terms St. John's wort, hypericum, herb, in vitro, cytochrome P450, and drug interactions. Little in vitro or in vivo data on St John's wort or other herb-drug interactions is available and current in vitro methods for screening conventional medications may have limited applications to herbal agents which generally have numerous constituents of unknown pharmacokinetics and pharmacology. However, available data from clinical studies and case reports suggests that St. John's wort is unlikely to inhibit cytochrome P450 (CYP) 3A4 or 2D6, but is likely an inducer of CYP 3A4 and possibly the P-glycoprotein transporter. Examples of conventional medications which may undergo significant CYP 3A4 induction by St. John's wort include cyclosporine, indinavir, and oral contraceptives. The accumulating evidence of significant drug interactions with St. John's wort should serve as an example to clinicians to be aware of the potential for St. John's wort, and very likely, other herbal products to participate in important herb-drug interactions when used in combination with conventional medications. Concomitant use of herbal agents and conventional medications should generally be discouraged until further information is available. Additional research is urgently needed in this area.
...
PMID:The emerging recognition of herb-drug interactions with a focus on St. John's wort (Hypericum perforatum). 1239 70

P-glycoprotein, the most extensively studied ATP-binding cassette (ABC) transporter, functions as a biological barrier by extruding toxins and xenobiotics out of cells. In vitro and in vivo studies have demonstrated that P-glycoprotein plays a significant role in drug absorption and disposition. Because of its localisation, P-glycoprotein appears to have a greater impact on limiting cellular uptake of drugs from blood circulation into brain and from intestinal lumen into epithelial cells than on enhancing the excretion of drugs out of hepatocytes and renal tubules into the adjacent luminal space. However, the relative contribution of intestinal P-glycoprotein to overall drug absorption is unlikely to be quantitatively important unless a very small oral dose is given, or the dissolution and diffusion rates of the drug are very slow. This is because P-glycoprotein transport activity becomes saturated by high concentrations of drug in the intestinal lumen. Because of its importance in pharmacokinetics, P-glycoprotein transport screening has been incorporated into the drug discovery process, aided by the availability of transgenic mdr knockout mice and in vitro cell systems. When applying in vitro and in vivo screening models to study P-glycoprotein function, there are two fundamental questions: (i) can in vitro data be accurately extrapolated to the in vivo situation; and (ii) can animal data be directly scaled up to humans? Current information from our laboratory suggests that in vivo P-glycoprotein activity for a given drug can be extrapolated reasonably well from in vitro data. On the other hand, there are significant species differences in P-glycoprotein transport activity between humans and animals, and the species differences appear to be substrate-dependent. Inhibition and induction of P-glycoprotein have been reported as the causes of drug-drug interactions. The potential risk of P-glycoprotein-mediated drug interactions may be greatly underestimated if only plasma concentration is monitored. From animal studies, it is clear that P-glycoprotein inhibition always has a much greater impact on tissue distribution, particularly with regard to the brain, than on plasma concentrations. Therefore, the potential risk of P-glycoprotein-mediated drug interactions should be assessed carefully. Because of overlapping substrate specificity between cytochrome P450 (CYP) 3A4 and P-glycoprotein, and because of similarities in P-glycoprotein and CYP3A4 inhibitors and inducers, many drug interactions involve both P-glycoprotein and CYP3A4. Unless the relative contribution of P-glycoprotein and CYP3A4 to drug interactions can be quantitatively estimated, care should be taken when exploring the underlying mechanism of such interactions.
...
PMID:Role of P-glycoprotein in pharmacokinetics: clinical implications. 1248 79

P-glycoprotein (P-gp), the most extensively studied ATP-binding cassette transporter, functions as a biological barrier by extruding toxic substances and xenobiotics out of cells. In vitro and in vivo studies have demonstrated that P-gp plays a significant role in drug absorption and disposition. Like cytochrome P450 enzymes, inhibition and induction of P-gp have been reported as the causes of drug-drug interactions. Because many prototypic inhibitors and inducers affect both CYP3A4 and P-gp, many drug interactions caused by these inhibitors and inducers involve these two systems. Clinically, it is very difficult to quantitatively differentiate P-gp-mediated drug interactions versus CYP3A4-mediated drug interactions, unless their relative contributions can be accurately estimated. Therefore, care should be exercised when interpreting drug interaction data and exploring the underlying mechanisms of drug interactions.
...
PMID:Drug-drug interaction mediated by inhibition and induction of P-glycoprotein. 1253 74


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

---