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)

1. The presence of inhibitors of drug efflux transporters, such as P-glycoprotein (P-gp), in grapefruit juice (GFJ) was confirmed based on the uptake of [(3)H]-vinblastine (VBL) by Caco-2 cells. 2. The uptake of [(3)H]-VBL by Caco-2 cells was significantly increased by the ethyl acetate extract of GFJ as well as by cyclosporin A. The extract was separated on a Cosmosil column and the eluate with 60% methanol increased [(3)H]-VBL uptake, while the activity to inhibit CYP3A4 was greatest in the 70 and 80% eluates. 3. These results show that the major inhibitor of efflux transport of VBL is different from that of CYP3A4. 4. Further separation of the 60% methanol eluate afforded dihydroxybergamottin (DHBG). Both ethyl acetate extract of GFJ and DHBG increased steady-state [(3)H]-VBL uptake by LLC-GA5-COL300 cells. Besides DHBG, other furanocoumarins contained in GFJ, such as bergamottin, FC726, bergaptol and bergapten, increased the steady-state uptake of [(3)H]-VBL by Caco-2 cells. 5. The order of inhibitory potency of these compounds was FC726>DHBG>bergamottin>bergapten>bergaptol . While, the IC(50) values for inhibition of CYP3A4 were 0.075, 0.45, 1.0, 1.0 and >20 microM, respectively. Bergaptol specifically inhibited VBL efflux. 6. DHBG was thus identified as a candidate for inhibitors of VBL transport, together with other furanocoumarins. Moreover, partly involvement of the P-gp inhibition was suggested. 7. Therefore, the inhibition of efflux transport of drugs as well as of drug metabolism by CYP3A4 could be an important cause of drug-GFJ interaction.
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PMID:Effect of furanocoumarin derivatives in grapefruit juice on the uptake of vinblastine by Caco-2 cells and on the activity of cytochrome P450 3A4. 1090 78

We have examined whether the expression levels of the intestinal absorptive barriers, MDR1 gene product P-glycoprotein and cytochrome P450 IIIA4 (CYP3A4), correlate with the trough levels of orally administered tacrolimus in a recipient of small bowel transplant for 4 months. By using a competitive polymerase chain reaction, the expression of MDR1 messenger RNA (mRNA) and CYP3A4 mRNA by intestinal cells in a part of the mucosa biopsy specimen was evaluated. The average mRNA expression levels of MDR1 and CYP3A4 were 8.6 and 39.6 amol/microg total RNA, respectively. Both the MDR1 and CYP3A4 mRNA levels changed markedly throughout this period. The tacrolimus concentration/dose ratio correlated well with the mRNA expression level of MDR1, but not CYP3A4. These results suggested that intestinal P-glycoprotein rather than CYP3A4 is a good probe to predict the intraindividual variation in the tacrolimus pharmacokinetics during immunosuppressant therapy after small bowel transplantation.
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PMID:Effect of intestinal P-glycoprotein on daily tacrolimus trough level in a living-donor small bowel recipient. 1094 21

Our previous report showed that L754.394 and valspodar (PSC833) are potent inhibitors of midazolam hydroxylation in human jejunum microsomes and vectorial transport of vinblastine in Caco-2 cells, respectively. In the present study, to directly examine the interactions of these compounds as well as other substrates with CYP3A4 and P-glycoprotein (P-gp), we performed in vitro inhibition studies using recombinant CYP3A4-expressed microsomes and an MDR1-transfected cell line, LLC-MDR1, respectively. In CYP3A4-expressed microsomes, both L754.394 and ketoconazole, at a concentration less than 0.5 microM, are the most potent inhibitors of the formation of 1'-hydroxymidazolam, a major metabolite of midazolam formed by CYP3A4. The greatest inhibitory effect on the transcellular transport of digoxin in LLC-MDR1 cells was observed in the presence of valspodar (<0.1 microM), followed by verapamil. From a comparison of the IC(50) values, it was shown that L754.394 and valspodar exhibited the highest selectivity for CYP3A4 and P-gp, respectively. To demonstrate such specificity, both midazolam hydroxylation and digoxin transport were observed in CYP3A4 transfected Caco-2 cells, which coexpress both P-gp and CYP3A4, in the presence or absence of L754.394 (0.5 microM) and valspodar (1.0 microM). L754.394 almost completely inhibited midazolam hydroxylation, but not digoxin transport, whereas almost complete inhibition of digoxin transport was observed in the presence of valspodar, but inhibition of the hydroxylation was minimal. Thus, the present study has demonstrated that L754.394 has a specific inhibitory effect on CYP3A4, whereas valspodar is specific for P-gp.
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PMID:Selective inhibition of human cytochrome P450 3A4 by N-[2(R)-hydroxy-1(S)-indanyl]-5-[2(S)-(1, 1-dimethylethylaminocarbonyl)-4-[(furo[2, 3-b]pyridin-5-yl)methyl]piperazin-1-yl]-4(S)-hydroxy-2(R)-phenylmethy lpentanamide and P-glycoprotein by valspodar in gene transfectant systems. 1099 46

Some compounds used for phenotyping of cytochrome P450s are substrates of P-glycoprotein (pgp). It is likely that in these cases, the level of pgp modulates the metabolism of in vivo probes. To address this important issue, we have analyzed the effects of pgp on CYP3A4-mediated reactions in two newly established cell lines (3A4/HR/MDR(-) and 3A4/HR/MDR(+)), which express CYP3A4 in the absence and presence of pgp, respectively. In cultured cells, the presence of pgp increased the apparent K(m) for the 6beta-hydroxylase activity of CYP3A4 toward testosterone and cortisol by a factor of 1.7 and 4, respectively. These steroids are poor and good substrates of pgp, respectively, and cortisol 6beta-hydroxylase has been frequently used as an in vivo probe for CYP3A4. Interestingly, we also found that pgp modulated the inhibition of CYP3A4-mediated metabolism by several compounds in intact cells. Although quinidine inhibited testosterone 6beta-hydroxylase activity in membranes or in intact cells that expressed recombinant CYP3A4 in the absence of pgp, low concentrations of this compound increased CYP3A4 activity in intact cells that expressed pgp. These results imply that pharmacokinetic drug-drug interactions involving CYP3A4 can be influenced by pgp.
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PMID:Modulation of P450 CYP3A4-dependent metabolism by P-glycoprotein: implications for P450 phenotyping. 1116 Jun 17

It is generally known that the substrates and/or inhibitors of cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) overlap with each other. In intestinal epithelial cells, it is surmised that the metabolites coexist with their parent drug. However, most studies on P-gp did not take the effects of those metabolites into consideration. Therefore, in the present study, we investigated the inhibitory effects of five substrates of CYP3A4 (nifedipine, testosterone, midazolam, amiodarone, and azelastine) and their metabolites on the P-gp-mediated transcellular transport. The transcellular transports of [(3)H]daunorubicin or [(3)H]digoxin by monolayers of LLC-GA5-COL150 cells in which P-gp was overexpressed were measured in the presence or absence of the CYP3A4 substrates and their metabolites. Nifedipine, testosterone, midazolam, and their metabolites exhibited no effects on the P-gp-mediated transport of [(3)H]daunorubicin and [(3)H]digoxin. On the other hand, the transport of [(3)H]daunorubicin was strongly inhibited by amiodarone, desethylamiodarone, azelastine, and desmethylazelastine, with IC(50) values of 22.5, 15.4, 16.0 and 11.8 microM, respectively. The transport of [(3)H]digoxin was also strongly inhibited by these compounds, with IC(50) values of 45.6, 25.2, 30.0 and 41.8 microM, respectively. Another metabolite of azelastine, 6-hydroxyazelastine, exhibited no effects on these transports. It was suggested that the CYP3A4 metabolites of which their parent drug exhibited inhibition on the P-gp-mediated transport are possibly also inhibitors. It would be possible more complicated drug-drug interactions would be caused by the metabolites as well as their parent drugs in the liver and the intestine via the inhibition of CYP3A4 and P-gp.
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PMID:Inhibitory effects of CYP3A4 substrates and their metabolites on P-glycoprotein-mediated transport. 1123 Nov 18

The low oral bioavailability of the HIV protease inhibitor (HPI) saquinavir is dramatically increased by coadministration of the HPI ritonavir. Because saquinavir and ritonavir are substrates and inhibitors of both the drug transporter P-glycoprotein (P-gp) and of the metabolizing enzyme CYP3A4, we wanted to sort out whether the ritonavir effect is primarily mediated by inhibition of CYP3A4 or P-gp or both. P-gp is known to limit the bioavailability, brain, testis, and fetal penetration of its substrates, so effective inhibition of P-gp by ritonavir in vivo might open up pharmacological sanctuary sites for saquinavir, with the potential of beneficial effects on therapy, but also of increased toxicity. In vitro, P-gp-mediated transport of saquinavir and ritonavir was only moderately inhibited by both HPIs compared with the potent P-gp inhibitor PSC833. When [(14)C]saquinavir was orally coadministered with a maximum tolerated dose of ritonavir to wild-type and P-gp-deficient mice, saquinavir bioavailability was dramatically increased in both strains, but P-gp still limited the oral bioavailability of saquinavir, and its penetration into brain and fetus. These data indicate that in vivo, ritonavir is a relatively poor P-gp inhibitor. The highly increased bioavailability of saquinavir because of ritonavir coadministration most likely results from reduced saquinavir metabolism. Importantly, our data indicate that it is unlikely that ritonavir coadministration will substantially affect the contribution of P-gp to pharmacological sanctuary sites such as brain, testis, and fetus. Thus, if one wanted to effectively open these sites for therapeutic purposes, more efficient P-gp inhibitors should be applied.
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PMID:P-glycoprotein limits oral availability, brain, and fetal penetration of saquinavir even with high doses of ritonavir. 1125 25

Intestinal phase I metabolism and active extrusion of absorbed drug have only recently been recognized as major determinants of oral drug bioavailability. Both CYP3A4, the major phase I drug metabolizing enzyme in humans, and the multidrug efflux pump, P-glycoprotein (P-gp), are present at high levels in the villus enterocytes of the small intestine, the primary site of absorption for orally administered drugs. Moreover, these proteins are induced by many of the same compounds and demonstrate a broad overlap in substrate and inhibitor specificities, suggesting that they act as a concerted barrier to drug absorption. Clinical studies have demonstrated that inhibition of CYP3A4-mediated intestinal metabolism can significantly improve the oral bioavailability of a wide range of drugs. Intestinal P-gp is a major route of elimination for both orally and intravenously administered anticancer drugs in animal models, and experiments with the Caco-2 cell line have provided strong evidence that inhibition of intestinal P-gp is another means by which oral drug bioavailability could be enhanced.
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PMID:Active secretion and enterocytic drug metabolism barriers to drug absorption. 1125 35

Inflammation and infection may have the potential to increase the bioavailability of drugs. This effect could be because of a reduced metabolism of xenobiotics in the liver and/or the intestines, or because of alterations in small intestinal permeability, mucosal flow, and expression of drug efflux transporters such as P-glycoprotein (Pgp). To assess the impact on intestinal epithelium of some proinflammatory cytokines and macrophages on permeability and mRNA expression of CYP3A4 and MDRI (multidrug resistance, coding for Pgp), we used the Caco-2 cell line as a model. Exposure to proinflammatory cytokines and macrophages decreased the mRNA expression of CYP3A4 and increased the expression of MDR1 mRNA in the Caco-2 cells. In parallel, the cell layer permeability, as measured by sodium fluorescein flux, increased for all cytokine and macrophage treatments, whereas the effect on transepithelial electrical resistance (TEER) varied. Our findings suggest that inflammation and infection trigger several different cellular responses that may affect drug bioavailability; that is hampered CYP3A4 expression, increased permeability of the epithelial cell layer, and enhanced Pgp-mediated counteractive transport.
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PMID:Cytokines influence mRNA expression of cytochrome P450 3A4 and MDRI in intestinal cells. 1128 8

Intestinal P-glycoprotein, which is encoded by the MDR1 gene, plays an important role in the absorption and presystemic elimination of many xenobiotics. Hence, an understanding of the factors regulating its expression and function is of substantial interest. In addition to genetic factors, exposure to drugs such as rifampin can profoundly affect its expression. So far, the mechanisms by which rifampin induces MDR1 expression are poorly understood. Recent studies demonstrate that the nuclear receptor PXR (pregnane X receptor) is involved in xenobiotic induction of CYP3A4. Because CYP3A4 and MDR1 are often co-induced, we investigated whether a similar mechanism is also involved in MDR1 induction. The human colon carcinoma cell line LS174T was used as an intestinal model to study induction because in these cells the endogenous MDR1 gene is highly inducible by rifampin. The 5'-upstream region of human MDR1 was examined for the presence of potential PXR response elements. Several binding sites were identified that form a complex regulatory cluster at about -8 kilobase pairs. Only one DR4 motif within this cluster is necessary for induction by rifampin. We conclude that induction of MDR1 is mediated by a DR4 motif in the upstream enhancer at about -8 kilobase pairs, to which PXR binds.
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PMID:Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. 1129 22

Fluvastatin, the first fully synthetic HMG-CoA reductase inhibitor, has been shown to reduce cholesterol in patients with hyperlipidaemia, to prevent subsequent coronary events in patients with established coronary heart disease, and to alter endothelial function and plaque stability in animal models. Fluvastatin is relatively hydrophilic, compared with the semisynthetic HMG-CoA reductase inhibitors, and, therefore, it is extensively absorbed from the gastrointestinal tract. After absorption, it is nearly completely extracted and metabolised in the liver to 2 hydroxylated metabolites and an N-desisopropyl metabolite, which are excreted in the bile. Approximately 95% of a dose is recovered in the faeces, with 60% of a dose recovered as the 3 metabolites. The 6-hydroxy and N-desisopropyl fluvastatin metabolites are exclusively generated by cytochrome P450 (CYP) 2C9 and do not accumulate in the blood. CYP2C9, CYP3A4, CYP2C8 and CYP2D6 form the 5-hydroxy fluvastatin metabolite. Because of its hydrophilic nature and extensive plasma protein binding, fluvastatin has a small volume of distribution with minimal concentrations in extrahepatic tissues. The pharmacokinetics of fluvastatin are not influenced by renal function, due to its extensive metabolism and biliary excretion; limited data in patients with cirrhosis suggest a 30% reduction in oral clearance. Age and gender do not appear to affect the disposition of fluvastatin. CYP3A4 inhibitors (erythromycin, ketoconazole and itraconazole) have no effect on fluvastatin pharmacokinetics, in contrast to other HMG-CoA reductase inhibitors which are primarily metabolised by CYP3A and are subject to potential drug interactions with CYP3A inhibitors. Coadministration of fluvastatin with gastrointestinal agents such as cholestyramine, and gastric acid regulating agents (H2 receptor antagonists and proton pump inhibitors), significantly alters fluvastatin disposition by decreasing and increasing bioavailability, respectively. The nonspecific CYP inducer rifampicin (rifampin) significantly increases fluvastatin oral clearance. In addition to being a CYP2C9 substrate, fluvastatin demonstrates inhibitory effects on this isoenzyme in vitro and in vivo. In human liver microsomes, fluvastatin significantly inhibits the hydroxylation of 2 CYP2C9 substrates, tolbutamide and diclofenac. The oral clearances of the CYP2C9 substrates diclofenac, tolbutamide, glibenclamide (glyburide) and losartan are reduced by 15 to 25% when coadministered with fluvastatin. These alterations have not been shown to be clinically significant. There are inadequate data evaluating the potential interaction of fluvastatin with warfarin and phenytoin, 2 CYP2C9 substrates with a narrow therapeutic index, and caution is recommended when using fluvastatin with these agents. Fluvastatin does not appear to have a significant effect on other CYP isoenzymes or P-glycoprotein-mediated transport in vivo.
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PMID:Clinical pharmacokinetics of fluvastatin. 1136 92


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