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)

Atazanavir (ATV) is a low oral bioavailability (BA) compound and, clinically, is generally coadministrated with ritonavir (RTV), which boosts the oral BA of ATV by inhibiting cytochrome P450 (CYP) 3A, and P-glycoprotein (Pgp) via the same metabolic pathway. However, depending on pharmacokinetic interaction, RTV-boosted ATV has great potential for other comedication. In this study we demonstrated the pharmaceutical approach to BA improvement of ATV without RTV in rats, based on the solid dispersion system using sodium lauryl sulfate (SLS) as a carrier and Gelucire 50/13 as an absorption enhancer. ATV solid dispersions in SLS were prepared by a conventional solvent method and, at ratios of ATV to SLS of 1 : 2 and 1 : 3, were demonstrated to form an amorphous state in powder X-ray diffraction (PXRD) analysis and exhibited 2.26- and 2.36-fold improvement in a dissolution test in comparison to bulk ATV, respectively. After oral administration to rats, ATV solid dispersion in SLS at a ratio of 1 : 2 showed a 3.5-fold increase in BA compared with bulk ATV. Moreover, the addition of Gelucire 50/13 to ATV solid dispersion, at a total ratio of Gelucire 50/13, ATV and SLS 1 : 1 : 2 gave 7.0- and 4.7-fold increase in Cmax and BA compared with bulk ATV, respectively, when the relative BA to RTV-boosted ATV reached 93%. The results in this study proved that a pharmaceutical approach could improve the bioavailability of ATV without pharmacokinetic interaction with RTV.
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PMID:Pharmaceutical approach to HIV protease inhibitor atazanavir for bioavailability enhancement based on solid dispersion system. 1740 12

Mitoquinone (MitoQ(10) mesylate) is a mitochondria-targeted antioxidant formulated for oral administration in the treatment of neurodegenerative diseases. We have investigated the absorption and metabolism of MitoQ(10) in Caco-2 cell monolayers. The intracellular accumulation of MitoQ(10) was 18-41% of the total amount of MitoQ(10) added. Some of the intracellular MitoQ(10) was reduced to mitoquinol and subsequently metabolized to glucuronide and sulfate conjugates. Transport of MitoQ(10) was polarized with the apparent permeability (P(app)) from basolateral (BL) to apical (AP) (P(appBL-->AP)) being >2.5-fold the P(app) from apical to basolateral (P(appAP-->BL)). In the presence of 4% bovine serum albumin on the basolateral side, the P(appAP-->BL) value increased 7-fold compared with control. The P(appBL-->AP) value decreased by 26, 31 and 61% in the presence of verapamil 100 microM, ciclosporin 10 and 30 microM, respectively, whereas the P(appAP-->BL) value increased 71% in the presence of ciclosporin 30 microM. Apical efflux of mitoquinol sulfate and mitoquinol glucuronide conjugates was significantly decreased by ciclosporin 30 microM and the breast cancer receptor protein (BCRP) inhibitor, reserpine 25 microM, respectively. These results suggested that the bioavailability of MitoQ(10) may be limited by intracellular metabolism and the action of P-glycoprotein and BCRP. However, the dramatic increase in absorptive P(app) in the presence of bovine serum albumin on the receiver side suggests these barrier functions may be less significant in-vivo.
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PMID:Transport and metabolism of MitoQ10, a mitochondria-targeted antioxidant, in Caco-2 cell monolayers. 1743 Jun 33

Treatment regimens combining moxifloxacin and rifampin for drug-susceptible tuberculosis are being studied intensively. However, rifampin induces enzymes that transport and metabolize moxifloxacin. We evaluated the effect of rifampin and the human multidrug resistance gene (MDR1) C3435T polymorphisms (P-glycoprotein) on moxifloxacin pharmacokinetic parameters. This was a single-center, sequential design study with 16 volunteers in which sampling was performed after four daily oral doses of moxifloxacin (400 mg) and again after 10 days of combined rifampin (600 mg) and moxifloxacin. After daily coadministration of rifampin, the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) for moxifloxacin decreased 27%. Average bioequivalence between moxifloxacin coadministered with rifampin and moxifloxacin alone was not demonstrated: the ratio of geometric means (RGM) of the moxifloxacin AUC(0-24) was 73.3 (90% confidence intervals [CI], 64.3, 83.5) (total P value, 0.87 for two one-sided t tests). Peak moxifloxacin concentrations, however, were equivalent: the RGM of the maximum concentration of the drug in serum was 93.6 (90% CI, 80.2, 109.3) (total P value, 0.049). Concentrations of the sulfate conjugate metabolite of moxifloxacin were increased twofold following rifampin coadministration (AUC(0-24), 1.29 versus 2.79 mug.h/ml). Concomitant rifampin administration resulted in a 27% decrease in the mean moxifloxacin AUC(0-24) and a marked increase in the AUC(0-24) of the microbiologically inactive M1 metabolite. Additional studies are required to understand the clinical significance of the moxifloxacin-rifampin interaction.
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PMID:Effects of rifampin and multidrug resistance gene polymorphism on concentrations of moxifloxacin. 1751 35

Ferulic acid is an important antioxidant found in food, beverages, supplements, and herbal medicines. However, its mechanism of absorption in the colon has never been examined, even though this is its main site of in vivo absorption. Ferulic acid was efficiently transported as the free form through an in vitro model for the colonic epithelium consisting of cocultured Caco-2 and mucus-producing HT29-MTX cells, with only a small amount transported as feruloyl-glucuronide or sulfate, together with some free dihydroferulic acid. This pattern of metabolism and permeation was also seen with the use of rat everted ascending and descending colon sacs. In the cell model, free ferulic acid permeated by passive diffusion, as judged by the linearity of the uptake over time and nonsaturable concentration dependence. The permeation was independent of tight junctions but strongly linked to the hydrophobicity of the different phenolic acids tested, suggesting a transcellular rather than a paracellular transport. Using inhibitors, we showed that only a small proportion (<20%) of the free ferulic acid transport was carrier-mediated. The production of metabolites in the basal chamber was lowered by 3-[[3-[2-(7-chloroquinolin-2-yl)-vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid (MK571) and increased by cyclosporin A, implying an involvement of multidrug resistance protein and P-glycoprotein transporters in the efflux of metabolites, respectively to the serosal and luminal sides. These results show that the form of ferulic acid available to the blood after passage across the colonic barrier would be mainly the free form, together with only a small percentage of conjugated and reduced ferulic acid.
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PMID:Transport and metabolism of ferulic acid through the colonic epithelium. 1795 26

Multidrug resistance (MDR) is one of the major obstacles limiting the efficacy of cancer chemotherapy. Identification of new and effective MDR reversal agents is needed. In this study, the effects of polyoxyethylene 40 stearate (PS40) on MDR were evaluated via the transport of the P-glycoprotein (P-gp) substrate vinblastine sulfate (VBL) through Caco-2 cell monolayers and rat intestine tissue. The effects of PS40 on the antitumor activity of VBL were examined through 3-(4,5)-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay and multidrug-resistant tumor-bearing mice. Results of the transport experiments showed that PS40 reduced VBL efflux. The cytotoxicity of vinblastine to K562/ADR cells was significantly enhanced when the cells were cotreated with 100 or 150 microg/mL PS40. In vivo data revealed that average tumor volume and average tumor weight were significantly less in the VBL+PS40 group than in the VBL group. The inhibition rate for tumor growth was increased from 0.06 (VBL group) to 0.84 (VBL+PS40 group). These results suggest that PS40 may be a potentially useful adjuvant to enhance the therapeutic effects of P-gp substrates.
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PMID:Polyoxyethylene 40 stearate modulates multidrug resistance and enhances antitumor activity of vinblastine sulfate. 1817 Sep 79

Metabolism and transport from intestinal cells back into the lumen by ATP-binding cassette (ABC) transporters is believed to limit the bioavailability of flavonoids. We studied metabolism and transport of the citrus flavonoid hesperetin, the aglycone of hesperidin, using a two-compartment transwell Caco-2 cell monolayer system, simulating the intestinal barrier. The role of apically located ABC transporters P-glycoprotein (MDR1/ABCB1), multidrug resistance protein 2 (ABCC2), and breast cancer resistance protein (BCRP/ ABCG2) in the efflux of hesperetin and its metabolites was studied by coadministration of compounds known to inhibit several classes of ABC transporters, including cyclosporin A, GF120918 [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide], Ko143 [3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indol-3-yl)-propionic acid tert-butyl ester], MK571 (3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid), and PSC-833 (Valspodar). Apically applied hesperetin (10 microM) was metabolized into hesperetin 7-O-glucuronide and hesperetin 7-O-sulfate, identified using high-performance liquid chromatographydiode array detector (DAD), ultraperformance liquid chromatography-DAD-tandem mass spectrometry, and authentic standards, which were transported predominantly to the apical side of the Caco-2 cell monolayer (1.12 cm(2)), at average (S.D.) rates of 14.3 (3.7) and 2.1 (0.8) pmol/min/monolayer, respectively. Hesperetin aglycone also permeated to the basolateral side, and this process was unaffected by the inhibitors used, possibly implying a passive diffusion process. Inhibition studies, however, showed that efflux of hesperetin conjugates to the apical side involved active transport, which from the pattern of inhibition appeared to involve mainly BCRP. Upon inhibition by the BCRP inhibitor Ko143 (5 micro M), the apical efflux of hesperetin conjugates was 1.9-fold reduced (p <or= 0.01), and transport to the basolateral side was 3.1-fold increased (p <or= 0.001). These findings elucidate a novel pathway of hesperetin metabolism and transport and show that BCRP-mediated transport could be a limiting step for hesperetin bioavailability.
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PMID:Metabolism and transport of the citrus flavonoid hesperetin in Caco-2 cell monolayers. 1851 33

AZT (3'-azido-3'-deoxythymidine; zidovudine), which is used for the prevention of mother-to-child transmission of HIV-1, is transplacentally transferred to the fetus across the blood-placenta barrier, which is composed of syncytiotrophoblasts. We recently showed that apical uptake of AZT by syncytiotrophoblasts is mediated by saturable transport system(s) in the TR-TBT 18d-1 cell line, and the cellular accumulation of AZT was increased in the presence of dehydroepiandrosterone sulfate (DHEAS). Here, we aimed to clarify the mechanism of this effect of DHEAS. Inhibitors of efflux transporters, including breast cancer resistance protein, P-glycoprotein, and multidrug resistance proteins, had little effect on the cellular accumulation of AZT in TR-TBT 18d-1. Kinetic study revealed that the rate constant for AZT uptake was greatly increased in the presence of 1 mM DHEAS. These results suggested that the effect of DHEAS was because of enhancement of the uptake process(es), rather than inhibition of efflux. When AZT uptake was analyzed according to the Michaelis-Menten equation, the estimated Michaelis constant, Km, for AZT uptake in the presence of 1 mM DHEAS was lower than that in its absence, whereas maximum uptake velocity, Vmax, and nonsaturable uptake clearance, kns, were similar in the presence and absence of DHEAS, indicating that DHEAS may change the recognition characteristics of the transporter for AZT in TR-TBT 18d-1. Thus, the increase of AZT uptake in TR-TBT 18d-1 cells in the presence of DHEAS was concluded to be because of a DHEAS-induced change in the affinity of AZT uptake system, although the transporter responsible for AZT uptake has not been identified.
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PMID:Enhancement of zidovudine uptake by dehydroepiandrosterone sulfate in rat syncytiotrophoblast cell line TR-TBT 18d-1. 1865 45

Previous experiments demonstrated that the biliary excretion of harmol sulfate (HS) was mediated by breast cancer resistance protein (Bcrp) and not by multidrug resistance-associated protein (Mrp)2 or P-glycoprotein in mice. However, recent reports suggested that species differences in hepatic canalicular transport mechanisms for a given substrate exist between mice and rats. In the present study, biliary excretion of HS was examined in perfused livers from mice and rats in the absence or presence of the P-glycoprotein and Bcrp inhibitor N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918). As expected, in mouse liver perfusions, the biliary excretion of HS was decreased approximately 3.5-fold by GF120918, consistent with previous reports of Bcrp-mediated HS biliary excretion. However, despite sufficient hepatic unbound concentrations of GF120918 to achieve extensive inhibition of Bcrp, the biliary excretion of HS was not decreased significantly in wild-type (50 +/- 12 versus 41 +/- 6%) or TR(-) (18 +/- 2 versus 16 +/- 3%) Wistar rats. In summary, biliary excretion of HS was mediated by a GF120918-sensitive mechanism in mice, previously elucidated as Bcrp. In contrast, the pathway responsible for HS biliary excretion in rats was not impaired by GF120918. Thus, transport mechanism(s) responsible for harmol sulfate biliary excretion appear to differ between mice and rats.
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PMID:Apparent differences in mechanisms of harmol sulfate biliary excretion in mice and rats. 1871 41

The human multidrug resistance gene MDR1 encodes a membrane-bound transporter P-glycoprotein (Pgp) that confers the drug resistance of cancer cells by mediating an ATP-dependent drug efflux transport. We and others have reported a number of functionally significant MDR1 variants, including G1199A and G1199T, that modulate cancer drug resistance and intracellular levels of antivirals. In this report, we describe a novel G571A variant of MDR1 detected in 6.4% of leukemia patients. Because this nucleotide modification gives rise to an amino acid change from Gly to Arg at the 191 amino acid position of Pgp, we have developed and characterized the functional affect of the G571A variant in stable, recombinant cells. Using six chemotherapeutic drugs, doxorubicin HCl, daunorubicin HCl, vinblastine sulfate, vincristine sulfate, taxanes (paclitaxel), and epipodophyllotoxin (etoposide, VP-16), we found that the MDR1(571A) variant selectively reduced the degree of Pgp-mediated resistance in drug-dependent manner. Although there was a minimal effect on doxorubicin and daunorubicin, the MDR1-dependent resistance on vinblastine, vincristine, paclitaxel, and etoposide was reduced by approximately 5-fold. The increased drug sensitivity in MDR1(571A), compared with MDR1(wt), paralleled the intracellular drug levels. These data suggest that individuals with this novel MDR1 variant, the 571A genotype, may be more sensitive to the specific anticancer drugs that are Pgp substrates.
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PMID:A novel human multidrug resistance gene MDR1 variant G571A (G191R) modulates cancer drug resistance and efflux transport. 1872 77

In previous reports, the effects of 12 Ca2+ antagonists on a multidrug resistant transporter, P-glycoprotein/MDR1, were evaluated in terms of those on MDR1-mediated transport of [3H]digoxin and the sensitivity of vinblastine sulfate or paclitaxel, and they were able to be classified into 4 subgroups based on their actions, as those with transport inhibition and sensitivity recovery, those with or without transport inhibition but marginal sensitivity recovery, and those without both. In this study, our previous findings were confirmed by the resistance against doxorubicin hydrochloride and daunorubicin hydrochloride, and by the recovery of [3H] vinblastine sulfate accumulation. Furthermore, it was found that the effects of 12 Ca2+ antagonists on the sensitivity recovery were also explained by the down-regulation of MDR1 mRNA, suggesting a novel mechanism to reverse the MDR1-mediated multidrug resistance.
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PMID:Reversal effects of Ca2+ antagonists on multidrug resistance via down-regulation of MDR1 mRNA. 1876 30


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