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:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The new H+/K(+)-ATPase inhibitor pantoprazole is extensively metabolized by the liver. As substituted benzimidazoles can interact with the cytochrome P450 system, the influence of pantoprazole on the steady-state pharmacokinetics of the calcium antagonist nifedipine was investigated. Nifedipine is widely used in the treatment of cardiovascular diseases and is mainly metabolized in the liver by CYP3A4. Additionally possible influence of gastric pH on the absorption of nifedipine is discussed. Twenty-four healthy volunteers (13 m/11 f) completed a randomized crossover study. As test they received orally 40 mg pantoprazole s.i.d. for 10 days and concomitantly 20 mg nifedipine sustained release (SR) b.i.d. from day 6 to 10. During the reference period 20 mg nifedipine SR were dosed b.i.d. for 5 days. Nifedipine and pantoprazole serum concentrations were measured over one dosing interval on the last day of each period. Lack of pharmacokinetic interaction was handled as an equivalence problem. The 90%-confidence intervals (CI) of the ratios of the primary characteristics AUC and Cmax of nifedipine were entirely within the equivalence range of 0.8-1.25. Hence no influence of pantoprazole on the pharmacokinetics of nifedipine was concluded, either by competition with the CYP3A4 or by the reduction of gastric acid secretion. As secondary criterion nifedipine had no relevant influence on the pantoprazole pharmacokinetic characteristics. All treatments were safe and well tolerated. No dose adjustment is required during concomitant treatment with nifedipine and pantoprazole.
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PMID:Pantoprazole does not interact with nifedipine in man under steady-state conditions. 879 8

The new H+/K+ -ATPase inhibitor pantoprazole is extensively metabolized by the liver. As substituted benzimidazoles can interact with the cytochrome P450 system, the influence of pantoprazole on the steady-state pharmacokinetics of the calcium antagonist nifedipine was investigated. Nifedipine is widely used in the treatment of cardiovascular diseases and is mainly metabolized in the liver by CYP3A4. Additionally possible influence of gastric pH on the absorption of nifedipine is discussed. Twenty-four healthy volunteers (13 m/11 f) completed a randomized crossover study. As test they received orally 40 mg pantoprazole s.i.d. for 10 days and concomitantly 20 mg nifedipine sustained release (SR) b.i.d. from day 6 to 10. During the reference period 20 mg nifedipine SR were dosed b.i.d. for 5 days. Nifedipine and pantoprazole serum concentrations were measured over one dosing interval on the last day of each period. Lack of pharmacokinetic interaction was handled as an equivalence problem. The 90%-confidence intervals (CI) of the ratios of the primary characteristics AUC and Cmax of nifedipine were entirely within the equivalence range of 0.8 - 1.25. Hence no influence of pantoprazole on the pharmacokinetics of nifedipine was concluded, either by competition with the CYP3A4 or by the reduction of gastric acid secretion. As secondary criterion nifedipine had no relevant influence on the pantoprazole pharmacokinetic characteristics. All treatments were safe and well tolerated. No dose adjustment is required during concomitant treatment with nifedipine and pantoprazole.
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PMID:Pantoprazole does not interact with nifedipine in man under steady-state conditions. 892 46

The role of P-glycoprotein in secretion of indinavir metabolites produced by CYP3A4 was evaluated in Caco-2 cells expressing CYP3A4. Metabolism of indinavir by CYP3A4 expressing Caco-2 cells grown on filters resulted in the formation of N-dealkylation products (M5 and M6) and hydroxylation of indinavir, which were preferentially secreted into the apical compartment. Apical secretion of the metabolites was inhibited by cyclosporin A (CsA) with all three classes of metabolites showing similar sensitivity to CsA, suggesting that they are all secreted by the same pathway. M6 stimulated P-glycoprotein (Pgp)-ATPase activity in a concentration-dependent manner. This stimulation was inhibited by the Pgp-specific monoclonal antibody C219. A method was developed to specifically inhibit Pgp using the monoclonal antibody UIC2 to determine whether Pgp efflux accounts for a significant proportion of the apical secretion of indinavir metabolites. UIC2 recognizes an extracellular transient conformational epitope that is stabilized by some Pgp substrates or by ATP depletion. Incubation of Caco-2 cells with UIC2 in the presence of 1 microM CsA resulted in 50 to 80% inhibition of Pgp-mediated vinblastine efflux, with no significant inhibition observed by UIC2 or CsA alone. Inhibition of Pgp in CYP3A4-expressing Caco-2 cells by UIC2 and 1 microM CsA resulted in a significant decrease in the apical secretion of M6, M5, and OH-indinavir and an increase in the amount of the metabolites secreted in the basolateral compartment and retained in the cytosol. These results are consistent with a role of Pgp in elimination of CYP3A4-generated metabolites and indicate that even relatively polar metabolites may be secreted from the cell by Pgp.
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PMID:P-glycoprotein-mediated efflux of indinavir metabolites in Caco-2 cells expressing cytochrome P450 3A4. 1140 58

The metabolism of 1-(2-methyl-4-methoxyphenyl)-4-[(3-hydroxypropyl)amino]-6-methyl-2,3-dihydropyrrolo[3,2c]quinoline (DBM-819), a new H(+)/K(+) ATPase inhibitor, has been studied by HPLC with spectrometric detection and on-line LC-electrospray mass spectrometry. In vitro incubation of DBM-819 with rat liver microsomes in the presence of NADPH resulted in the production of four metabolites (M1-4), whereas DBM-819 was oxidized to two metabolites, M2 and M4, by human liver microsomes. M2, M3 and M4 were identified as O-demethyl-DBM-819, 8-hydroxy-DBM-819 and N-dehydroxypropyl-DBM-819, respectively, based on LC/MS/MS analysis with authentic standards. M1 was tentatively identified as 1-(hydroxy-2-methyl-4-methoxyphenyl)-4-[(3-hydroxypropyl)amino]-6-methyl-2,3-dihydropyrrolo[3,2c]quinoline. Rat liver CYP1A1/2 catalyzed the oxidation of DBM-819 to 8-hydroxy-DBM-819 and N-dehydroxypropyl-DBM-819. Human CYP3A4 was a major isozyme for the formation of O-demethyl-DBM-819 as well as N-dehydroxypropyl-DBM-819.
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PMID:In vitro metabolism of a new H(+)/K(+) ATPase inhibitor DBM-819 in liver microsomes using HPLC and electrospray mass spectrometry. 1174 83

P-glycoprotein (Pgp) is a 170 kDa phosphorylated glycoprotein encoded by human MDR1 gene. It is responsible for the systemic disposition of numerous structurally and pharmacologically unrelated lipophilic and amphipathic drugs, carcinogens, toxins, and other xenobiotics in many organs, such as the intestine, liver, kidney, and brain. Like cytochrome P450s (CYP3A4), Pgp is vulnerable to inhibition, activation, or induction by herbal constituents. This was demonstrated by using an ATPase assay, purified Pgp protein or intact Pgp-expressing cells, and proper probe substrates and inhibitors. Curcumin, ginsenosides, piperine, some catechins from green tea, and silymarin from milk thistle were found to be inhibitors of Pgp, while some catechins from green tea increased Pgp-mediated drug transport by heterotropic allosteric mechanism, and St. John's wort induced the intestinal expression of Pgp in vitro and in vivo. Some components (e.g., bergamottin and quercetin) from grapefruit juice were reported to modulate Pgp activity. Many of these herbal constituents, in particular flavonoids, were reported to modulate Pgp by directly interacting with the vicinal ATP-binding site, the steroid-binding site, or the substrate-binding site. Some herbal constituents (e.g., hyperforin and kava) were shown to activate pregnane X receptor, an orphan nuclear receptor acting as a key regulator of MDR1 and many other genes. The inhibition of Pgp by herbal constituents may provide a novel approach for reversing multidrug resistance in tumor cells, whereas the stimulation of Pgp expression or activity has implication for chemoprotective enhancement by herbal medicines. Certain natural flavonols (e.g., kaempferol, quercetin, and galangin) are potent stimulators of the Pgp-mediated efflux of 7,12-dimethylbenz(a)-anthracene (a carcinogen). The modulation of Pgp activity and expression by these herb constituents may result in altered absorption and bioavailability of drugs that are Pgp substrates. This is exemplified by increased oral bioavailability of phenytoin and rifampin by piperine and decreased bioavailability of indinavir, tacrolimus, cyclosporine, digoxin, and fexofenadine by coadministered St. John's wort. However, many of these drugs are also substrates of CYP3A4. Thus, the modulation of intestinal Pgp and CYP3A4 represents an important mechanism for many clinically important herb-drug interactions. Further studies are needed to explore the relative role of Pgp and CYP3A4 modulation by herbs and the mechanism for the interplay of these two important proteins in herb-drug interactions.
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PMID:Herbal modulation of P-glycoprotein. 1507 39

KR-60436 ([1-(4-methoxy-2-methylphenyl)-4-[(2-hydroxyethyl)amino]-6-trifluoromethoxy-2,3-dihydropyrrolo [3,2-c]quinoline]) is a new reversible H+/K+-ATPase inhibitor. The isoforms of human liver cytochrome P450 (CYP) responsible for the hepatic transformation of KR-60436 is identified. Dihydropyrrole oxidation and O-demethylation are major pathways for the metabolism of KR-60436 in human liver microsomes, whereas N-dehydroxyethylation and hydroxylation are minor pathways. The specific CYP isozymes responsible for KR-60436 oxidation to four major metabolites, pyrrole-KR-60436, O-demethylpyrrole-KR-60436, N-dehydroxyethyl-KR-60436 and an active metabolite, O-demethyl-KR-60436 were identified using the combination of correlation analysis, immuno-inhibition, chemical inhibition in human liver microsomes and metabolism by expressed recombinant CYP enzymes. The inhibitory potency of KR-60436 on clinically major CYPs was investigated in human liver microsomes. The results show that CYP3A4 contributes to the oxidation of KR-60436 to pyrrole-KR-60436, O-demethylpyrrole-KR-60436 and N-dehydroxyethyl-KR-60436, and CYP2C9 and CYP2D6 play roles in demethylation of KR-60436 to form the active metabolite, O-demethyl-KR-60436. KR-60436 was found to inhibit potently the metabolism of CYP1A2 substrates.
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PMID:Characterization of human liver cytochrome P450 enzymes involved in the metabolism of a new H+/K+-ATPase inhibitor KR-60436. 1558 65

Reported adverse drug interactions with the popular herb kava have spurred investigation of the mechanisms by which kava could mediate these effects. In vivo and in vitro experiments were conducted to examine the effects of kava extract and individual kavalactones on cytochrome P450 (P450) and P-glycoprotein activity. The oral pharmacokinetics of the kavalactone, kawain (100 mg/kg), were determined in rats with and without coadministration of kava extract (256 mg/kg) to study the effect of the extract on drug disposition. Kawain was well absorbed, with >90% of the dose eliminated within 72 h, chiefly in urine. Compared with kawain alone, coadministration with kava extract caused a tripling of kawain AUC(0-8 h) and a doubling of C(max). However, a 7-day pretreatment with kava extract (256 mg /kg/day) had no effect on the pharmacokinetics of kawain administered on day 8. The 7-day pretreatment with kava extract only modestly induced hepatic P450 activities. The human hepatic microsomal P450s most strongly inhibited by kava extract (CYP2C9, CYP2C19, CYP2D6, CYP3A4) were inhibited to the same degree by a "composite" kava formulation composed of the six major kavalactones contained in the extract. K(i) values for the inhibition of CYP2C9 and CYP2C19 activities by methysticin, dihydromethysticin, and desmethoxyyangonin ranged from 5 to 10 microM. Kava extract and kavalactones (< or =9 microM) modestly stimulated P-glycoprotein ATPase activities. Taken together, the data indicate that kava can cause adverse drug reactions via inhibition of drug metabolism.
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PMID:Pharmacokinetics and disposition of the kavalactone kawain: interaction with kava extract and kavalactones in vivo and in vitro. 1603 48

Clinical findings indicate that co-administration of the isoxazolyl-penicillin flucloxacillin with cyclosporine may reduce the plasma concentrations of cyclosporine. We have explored in the present study if induction of cytochrome P450 3A4 or P-glycoprotein may offer a mechanistic explanation of the observed effects. Flucloxacillin is neither an inhibitor nor a substrate of drug metabolizing cytochrome P450 isoenzymes (CYP3A4, 1A2, 2C9, 2C19 and 2D6) or P-glycoprotein as shown by an in vitro assay for CYP inhibition, a fluorescent indicator assay for P-glycoprotein inhibition and a functional P-glycoprotein ATPase assay. However, incubation of human LS 180 colorectal adenocarcinoma cells with flucloxacillin led to a dose-dependent induction of MDR1 as well as of CYP3A4 mRNA, which was also confirmed in primary human hepatocytes. At high concentrations, flucloxacillin activated the human Pregnane-X-Receptor, PXR, a ligand-dependent transcription factor that is the target of many drugs that induce CYP3A4, with consequences for the metabolism of other drugs. Liver microsomes from control rats or rats, which received for 3 consecutive days 100 mg/kg of oral flucloxacillin, were used to study the metabolism and metabolite pattern of midazolam, a model substrate of CYP 3A4. There was a trend towards a higher intrinsic microsomal clearance of midazolam using microsomes from flucloxacillin treated rats. In addition, there was a significant increase in the formation of the principal midazolam metabolites 1-hydroxy midazolam, 4-hydroxy midazolam and 1,4-dihydroxy midazolam as compared to controls. These findings indicate that flucloxacillin has the potential to induce expression of both CYP3A4 as well as P-glycoprotein, most likely through activation of the nuclear hormone receptor PXR. This would offer an explanation for the observed clinical drug-drug interactions between the antibiotic and cyclosporine.
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PMID:Induction of cytochrome P450 3A4 and P-glycoprotein by the isoxazolyl-penicillin antibiotic flucloxacillin. 1647 2

To select the best drug for a patient, physicians can use pharmacogenomics to optimize the effective drug and to minimize adverse reactions. Many enzymes are involved in the pharmacokinetic and pharmacodynamic sources of cardiovascular drugs. Taking the antihypertensive drugs as an example, the variability in blood pressure response is very high in different individuals, some of them having an increase in blood pressure. The most important proteins involved in the patient response to a drug are cytochrome P450 (CYP) 2D6, CYP2C19, CYP3A4 and the ABCB1 transporter. These enzymes, at the origin of important side effects or drug interactions, are responsible, at a great extent, of the cardiovascular drug response variability. Genotyping of the most important CYP today is easy while no reliable tool has been developed for the ABC transporters ATPase dependent and linked to the other phase I and phase II enzymes. The second relevant group of enzymes are involved in pharmacodynamic action of cardiovascular drugs: enzymes of the renin-angiotensin system and enzymes of the lipid metabolism. Angiotensin converting enzyme (ACE) is the most studied target with a relevant insertion deletion polymorphism. Contradictory reported data could be explained by ethnic differences or patient sample size which are often too small.
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PMID:Enzymes and pharmacogenetics of cardiovascular drugs. 1736 1

Mammalian hepatic cytochromes P450 (P450s) are endoplasmic reticulum (ER)-anchored hemoproteins engaged in the metabolism of numerous xeno- and endobiotics. P450s exhibit widely ranging half-lives, utilizing both autophagic-lysosomal (ALD) and ubiquitin-dependent 26S proteasomal (UPD) degradation pathways. Although suicidally inactivated hepatic CYPs 3A and "native" CYP3A4 in Saccharomyces cerevisiae are degraded via UPD, the turnover of native hepatic CYPs 3A in their physiological milieu has not been elucidated. Herein, we characterize the degradation of native, dexamethasone-inducible CYPs 3A in cultured primary rat hepatocytes, using proteasomal (MG-132 and MG-262) and ALD [NH4Cl and 3-methyladenine (3-MA)] inhibitors to examine their specific degradation route. Pulse-chase with immunoprecipitation analyses revealed a basal 52% 35S-CYP3A loss over 6 h, which was stabilized by both proteasomal inhibitors. By contrast, no corresponding CYP3A stabilization was detected with either ALD inhibitor NH4Cl or 3-MA. Furthermore, MG-262-induced CYP3A stabilization was associated with its polyubiquitylation, thereby verifying that native CYPs 3A were also degraded via UPD. To identify the specific participants in this process, cellular proteins were cross-linked in situ with paraformaldehyde (PFA) in cultured hepatocytes. Immunoblotting analyses of CYP3A immunoprecipitates after PFA-cross-linking revealed the presence of p97, a cytosolic AAA ATPase instrumental in the extraction and delivery of ubiquitylated ER proteins for proteasomal degradation. Such native CYP3A-p97 interactions were greatly magnified after CYP3A suicidal inactivation (which accelerates UPD), and/or proteasomal inhibition, and were confirmed by proteomic and confocal immunofluorescence microscopic analyses. These findings clearly reveal that native CYPs 3A undergo UPD and implicate a role for p97 in this process.
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PMID:Characterization of the physiological turnover of native and inactivated cytochromes P450 3A in cultured rat hepatocytes: a role for the cytosolic AAA ATPase p97? 1755 Feb 36


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