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)

Drug-herb interactions can result from the modulation of the activities of cytochrome P450 (P450) and/or drug transporters. The effect of extracts and individual constituents of goldenseal, Ginkgo biloba (and its hydrolyzate), grape seed, milk thistle, and ginseng on the activities of cytochrome P450 enzymes CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 in human liver microsomes were determined using enzyme-selective probe substrates, and their effect on human P-glycoprotein (Pgp) was determined using a baculovirus expression system by measuring the verapamil-stimulated, vanadate-sensitive ATPase activity. Extracts were analyzed by HPLC to standardize their concentration(s) of constituents associated with the pharmacological activity, and to allow comparison of their effects on P450 and Pgp with literature values. Many of the extracts/constituents exerted > or = 50 % inhibition of P450 activity. These include those from goldenseal (normalized to alkaloid content) inhibiting CYP2C8, CYP2D6, and CYP3A4 at 20 microM, ginkgo inhibiting CYP2C8 at 10 microM, grape seed inhibiting CYP2C9 and CYP3A4 at 10 microM, milk thistle inhibiting CYP2C8 at 10 microM, and ginsenosides F1 and Rh1 (but not ginseng extract) inhibiting CYP3A4 at 10 microM. Goldenseal extracts/constituents (20 microM, particularly hydrastine) and ginsenoside Rh1 stimulated ATPase at about half of the activity of the model substrate, verapamil (20 microM). The data suggest that the clearance of a variety of drugs may be diminished by concomitant use of these herbs via inhibition of P450 enzymes, but less so by Pgp-mediated effects.
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PMID:An in vitro evaluation of cytochrome P450 inhibition and P-glycoprotein interaction with goldenseal, Ginkgo biloba, grape seed, milk thistle, and ginseng extracts and their constituents. 1761 34

N,N-diethyl-2-[4-(phenylmethyl) phenoxy] ethanamine (DPPE; tesmilifene) is a novel anti-histaminic and chemopotentiating agent that has a hormetic effect on DNA synthesis in MCF (Michigan Cancer Foundation)-7 human breast cancer cells in vitro and stimulates the growth of experimental tumors in rodents. In a prospectively randomized phase three trial (NCIC MA.19), 152 patients who were co-administered DPPE and doxorubicin survived 50% longer (P < 0.03) than 153 patients who were administered the same dose and schedule of doxorubicin alone. At clinically relevant in vitro concentrations that do not inhibit the P-glycoprotein (P-gp) pump, DPPE selectively sensitizes the cancer cells that express the multiple drug resistance phenotype, making them more susceptible to the cytotoxic effects of chemotherapeutic agents, including anthracyclines and taxanes. Based on its previously demonstrated interaction with histamine at CYP3A4, a P450 that metabolizes arachidonic acid, and its induction of high levels of prostacyclin in the gut of rodents, modulation by DPPE of the intracellular concentration of arachidonate products, such as hydroxyeicosatetraeinoic acids, implicated in increased cancer cell proliferation and metastasis, is postulated.
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PMID:N,N-diethyl-2-[4-(phenylmethyl) phenoxy] ethanamine (DPPE; tesmilifene), a chemopotentiating agent with hormetic effects on DNA synthesis in vitro, may improve survival in patients with metastatic breast cancer. 1848 Jan 39

N,N-Diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine (DPPE, tesmilifene), a potent chemopotentiating drug currently in Phase III clinical trials of metastatic breast cancer, increases cytotoxicity of anthracyclines and taxanes in a variety of multi-drug resistance expressing (MDR+) tumor cell lines in vitro; inhibits binding of histamine to CYP3A4, a lipid/prostanoid-regulatory P450; and modulates serum levels of HDL/LDL cholesterol and phospholipids in vivo. Since increased exposure of phosphatidylserine (PS) on the outer cell membrane leaflet is associated with apoptosis, increased clearance of dead cells by phagocytes and inhibition of the P-glycoprotein pump, the effect of DPPE on PS synthesis was assessed in vitro in a human breast cancer cell line. MCF-7 cells were incubated with 5 microM DPPE for 24 hr or 5 days, followed by addition of [1-(14)C]arachidonic acid for 4 hr; or [3H]serine for 8 hr. Compared to untreated cells, a 27-42% (p < 0.05) increase in [1-(14)C]arachidonic acid incorporated into all phospholipids, including a 1.9-fold increase (p < 0.05) in PS was observed in DPPE-treated cells. [3H]Serine incorporation into PS was elevated 37%, while the pool size of PS was elevated 23% (p < 0.05) in DPPE-treated cells, indicating elevated de novo PS biosynthesis. Annexin-5 binding studies indicated an elevation in exposure of PS on the surface of the plasma membrane in DPPE-treated cells. DPPE-treatment also resulted in N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine accumulation indicative of phospholipidosis-inducing potential. Thus, the chemopotentiating effect of DPPE may be due to its phospholipidosis-inducing potential and stimulation of PS synthesis leading to an increased exposure of PS on the cell surface which could potentially enhance cancer cell clearance by phagocytes.
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PMID:The phospholipidosis-lnducing potential of the chemopotentiating drug, N,N-Diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine (DPPE, tesmilifene) correlates with its stimulation of phosphatidylserine synthesis and exposure on the plasma membrane in MCF-7 breast cancer cells. 1860 31

New light has been shed on the mechanisms of action of colchicine in crystal-associated arthropathies. Colchicine, long used to treat gout, arrests microtubule assembly and inhibits many cellular functions. At micromolar concentrations, it suppresses monosodium urate crystal-induced NACHT-LRR-PYD-containing protein-3 (NALP3) inflammasome-driven caspase-1 activation, IL-1beta processing and release, and L-selectin expression on neutrophils. At nanomolar concentrations, colchicine blocks the release of a crystal-derived chemotactic factor from neutrophil lysosomes, blocks neutrophil adhesion to endothelium by modulating the distribution of adhesion molecules on the endothelial cells, and inhibits monosodium urate crystal-induced production of superoxide anions from neutrophils. Cyto-chrome P450 3A4, the multidrug transporter P-glycoprotein, and the drugs that bind these proteins influence its pharmacokinetics and pharmacodynamics. Trial evidence supports its efficacy in acute gout and in preventing gout flares, but it has narrow therapeutic index, and overdosage is associated with gastrointestinal, hepatic, renal, neuromuscular, and cerebral toxicity; bone marrow damage; and high mortality.
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PMID:Colchicine: its mechanism of action and efficacy in crystal-induced inflammation. 1863 31

In recent years, following the successful development of highly active antiretroviral therapy (HAART), several studies have evaluated potential differences between men and women in the course of HIV infection, response to treatment, and drug pharmacokinetics. A slightly lower HIV viral load in untreated women has been reported, particularly at higher CD4+ levels, but this difference does not translate into gender-specific recommendations concerning initiation of therapy. Data on drug response suggest similar response of treatment and similar outcomes in men and women, but female subjects appear to be more susceptible to adverse events related to antiretroviral treatment. Social and behavioural factors may determine gender differences in therapeutic adherence and treatment discontinuation. The available evidence on pharmacokinetics of antiretroviral drugs suggests higher exposure in women compared to men. The factors and mechanisms more likely to be clinically relevant in determining this difference are represented by body weight and composition, renal clearance, and P-glycoprotein activity. Many antiretroviral drugs influence P450 activity, and interactions are common. The results of the studies exploring gender differences in pharmacokinetics of anti-HIV drugs are often not consistent, but several mechanisms may be involved in determining a final difference, and it might be difficult to adjust for all potential confounders. Specific considerations are needed in the selection of anti-HIV regimens in pregnancy, which must ensure protection from both HIV transmission and adverse neonatal outcomes. In order to optimize treatment in all infected people with HIV, there is the need to conduct further research on gender differences in HIV therapeutics. To obtain this goal, specific studies should be designed and females' participation in both cohort studies and clinical trials should be promoted.
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PMID:Gender differences in the treatment of HIV infection. 1870 44

This study was to investigate the effect of kaempferol on the pharmacokinetics of etoposide after oral or intravenous administration of etoposide in rats. The oral (6 mg/kg) or intravenous (2 mg/kg) etoposide was administered to rats alone or 30 min after the oral kaempferol (1, 4, or 12 mg/kg) administration. Compared to the oral control group, the presence of kaempferol significantly (4 mg/kg, P < 0.05; 12 mg/kg, P < 0.01) increased the area under the plasma concentrationtime curve (AUC) and the peak concentration (C(max)) of the oral etoposide. Kaempferol decreased significantly (4 or 12 mg/kg, P < 0.05) the total body clearance (CL/F) of oral etoposide, while there was no significant change in the terminal halflife (t(1/2)), the elimination rate constant (K(el)) and the time to reach the peak concentration (T(max)) of etoposide in the presense of kaempferol. Consequently, the absolute bioavailability (AB%) of oral etoposide with kaempferol was significantly higher (4 mg/kg, P < 0.05; 12 mg/kg, P < 0.01) than those from the control group. Compared to the intravenous control group, the presence of kaempferol enhanced the AUC of intravenously administered etoposide, however, only presence of 12 mg/kg of kaempferol significant (P < 0.05) increased AUC of etoposide. The enhanced bioavailability of oral etoposide by kaempferol could have been due to an inhibition of cytochrom P450 (CYP) 3A and P-glycoprotein (P-gp) in the intestinal or decreased total body clearance in the liver by kaempferol. The dosage regimen of etoposide should be taken into consideration for potential drug interaction when combined with kaempferol or dietary supplements containing kaempferol in patients.
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PMID:Enhanced bioavailability of etoposide after oral or intravenous administration of etoposide with kaempferol in rats. 1918 86

Modern drug discovery chemical libraries contain a large number of molecular entities exhibiting low aqueous solubility, often necessitating the inclusion of solubilizing agents in preclinical models of absorption or metabolism. The objective of the present study was to investigate the effects of several commonly used polyethoxylated solubilizing agents on P450 (CYP) 3A and P-glycoprotein (P-gp) in the rat intestinal mucosa. Atenolol and verapamil were administered in the in situ perfused rat intestine or incubated with rat intestinal microsomes in the presence or absence of polyethylene glycol (PEG) 400 (2% or 20%, v/v) D-alpha-tocopheryl polyethylene glycol-1000 succinate (TPGS; 100 microg/mL), Cremophor EL (47.5 microg/mL) or polysorbate (Tween) 80 (25 microg/mL). Effects on the absorption of unchanged drug were minimal, with the exception of Tween 80 which caused a 5.0-fold increase in paracellular absorption. Rat intestinal CYP3A was significantly inhibited by PEG-400 and in situ, exceeded inhibition observed with ketoconazole. Cremophor and TPGS increased the fraction of norverapamil in the plasma, consistent with excipient-mediated inhibition of P-gp. These results suggest that caution be exercised when these solubilizing agents are included in preclinical oral dosing solutions as the perturbation of drug absorption barriers may heighten the risk of incorrectly classifying drug candidate PK-parameters.
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PMID:Absorption barriers in the rat intestinal mucosa. 3: Effects of polyethoxylated solubilizing agents on drug permeation and metabolism. 1965 Jan 19

Hepatocyte growth factor (HGF) is known to down-regulate expression of drug-detoxifying proteins such as cytochromes P450 (P450s) in human hepatocytes. The present study was designed to determine whether HGF may also impair expression of uptake and efflux drug transporters, which constitute important determinants of the liver detoxification pathway, such as P450s. Exposure of primary human hepatocytes to 20 ng/ml HGF for 48 h was found to down-regulate mRNA levels of major sinusoidal uptake transporters, including sodium taurocholate-cotransporting polypeptide (NTCP), organic anion-transporting polypeptide (OATP) 2B1, OATP1B1, organic cation transporter (OCT) 1, and organic anion transporter 2. HGF concomitantly reduced NTCP, OATP2B1, and OATP1B1 protein expression and NTCP, OATP, and OCT1 transport activities. With respect to efflux pumps, HGF decreased mRNA expression of the canalicular bile salt export pump, whereas that of the multidrug resistance (MDR) 1 gene was transiently increased. Moreover, Western blot analysis indicated that HGF up-regulated expressions of MDR1/P-glycoprotein and breast cancer resistance protein in human hepatocytes, whereas those of multidrug resistance gene-associated protein (MRP) 2 and MRP3 were unchanged. However, HGF prevented constitutive androstane receptor-related up-regulation of MRP2 occurring in phenobarbital-treated hepatocytes. Taken together, these data demonstrate that HGF differentially regulates transporter expression in human hepatocytes, i.e., it represses most of the sinusoidal uptake transporters, whereas expression of most of the efflux transporters is unchanged or increased. Such changes probably contribute to alterations of pharmacokinetics in patients with diseases associated with increased plasma levels of HGF such as fulminant hepatitis.
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PMID:Differential regulation of drug transporter expression by hepatocyte growth factor in primary human hepatocytes. 1966 Dec 16

(2S,3R,4R,5S,6R)-2-(3-(4-Ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyl-tetrahydro-2H-pyran-3,4,5-triol (dapagliflozin; BMS-512148) is a potent sodium-glucose cotransporter type II inhibitor in animals and humans and is currently under development for the treatment of type 2 diabetes. The preclinical characterization of dapagliflozin, to allow compound selection and prediction of pharmacological and dispositional behavior in the clinic, involved Caco-2 cell permeability studies, cytochrome P450 (P450) inhibition and induction studies, P450 reaction phenotyping, metabolite identification in hepatocytes, and pharmacokinetics in rats, dogs, and monkeys. Dapagliflozin was found to have good permeability across Caco-2 cell membranes. It was found to be a substrate for P-glycoprotein (P-gp) but not a significant P-gp inhibitor. Dapagliflozin was not found to be an inhibitor or an inducer of human P450 enzymes. The in vitro metabolic profiles of dapagliflozin after incubation with hepatocytes from mice, rats, dogs, monkeys, and humans were qualitatively similar. Rat hepatocyte incubations showed the highest turnover, and dapagliflozin was most stable in human hepatocytes. Prominent in vitro metabolic pathways observed were glucuronidation, hydroxylation, and O-deethylation. Pharmacokinetic parameters for dapagliflozin in preclinical species revealed a compound with adequate oral exposure, clearance, and elimination half-life, consistent with the potential for single daily dosing in humans. The pharmacokinetics in humans after a single dose of 50 mg of [(14)C]dapagliflozin showed good exposure, low clearance, adequate half-life, and no metabolites with significant pharmacological activity or toxicological concern.
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PMID:In vitro characterization and pharmacokinetics of dapagliflozin (BMS-512148), a potent sodium-glucose cotransporter type II inhibitor, in animals and humans. 1999 49

Photodynamic therapy (PDT) is a flexible multi-target therapeutic approach. One of the main requirements of successful PDT is sufficient intracellular concentration of an applicable photosensitizer. Mechanisms of anticancer drug elimination by tumour cells are mostly linked to the elevated expression and activity of P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), breast cancer resistance protein (BCRP) and P450 monooxygenases. The interaction of hypericin with this cell drug-defence system is still unclear. We report here for the first time increased activity of MRP1 and BCRP in HT-29 colon cancer cells treated with hypericin per se. On the contrary, pre-treatment with proadifen (SKF525A) affected the function of MRP1 and BCRP leading to increased hypericin content, which might indicate a possible link between proadifen and these ABC transporter proteins. Subsequent enhanced intracellular oxidative stress was accompanied by loss of mitochondrial membrane potential, activation of caspase-9 and -3, PARP cleavage and onset of apoptosis. In conclusion, our study suggests that drug efflux transporters MRP1 and BCRP affect the pharmacokinetics of hypericin in HT-29 colon adenocarcinoma cells, and the action of hypericin-mediated PDT (HY-PDT) should be modulated by pre-treatment with their specific inhibitors.
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PMID:Drug efflux transporters, MRP1 and BCRP, affect the outcome of hypericin-mediated photodynamic therapy in HT-29 adenocarcinoma cells. 2002 69


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