EC:1.14.13.97 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.14.13.97 (CYP3A4)
6,365 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lopinavir/ritonavir (LPV/RTV) is a CYP3A4 inhibitor and substrate; it also may induce cytochrome P-450 (CYP) isozymes. Phenytoin (PHT) is a CYP3A4 inducer and CYP2C9/CYP2C19 substrate. This study quantified the pharmacokinetic (PK) drug interaction between LPV/RTV and PHT. Open-label, randomized, multiple-dose, PK study in healthy volunteers. Subjects in arm A (n = 12) received LPV/RTV 400/100 mg twice daily (BID) (days 1-10), followed by LPV/RTV 400/100 mg BID + PHT 300 mg once daily (QD) (days 11-22). Arm B (n = 12) received PHT 300 mg QD (days 1-11), followed by PHT 300 mg QD + LPV/RTV 400/100 mg BID (days 12-23). Plasma samples were collected on day 11 and day 22; PK parameters were compared by geometric mean ratio (GMR, day 22:day 11). P values <0.05 were considered significant. Following PHT addition, LPV area under the concentration-time curve (AUC0-12h) decreased from 70.9 +/-37.0 to 49.6 +/- 25.1 microg.h/mL (GMR 0.67, P = 0.011) and C0h decreased from 6.0 +/- 3.2 to 3.6 +/- 2.3 microg/mL (GMR 0.54, P = 0.001). Following LPV/RTV addition, PHT AUC0-24h decreased from 191.0+/-89.2 to 147.8+/-104.5 microg.h/mL (GMR 0.69, P = 0.009) and C0h decreased from 7.0+/-4.0 to 5.3+/-4.1 microg/mL (GMR 0.66, P = 0.033). Concomitant LPV/RTV and PHT use results in a 2-way drug interaction. Phenytoin appears to increase LPV clearance via CYP3A4 induction, which is not offset by the presence of low-dose RTV. LPV/RTV may increase PHT clearance via CYP2C9 induction. Management should be individualized to each patient; dosage or medication adjustments may be necessary.
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PMID:Coadministration of lopinavir/ritonavir and phenytoin results in two-way drug interaction through cytochrome P-450 induction. 1524 56

Mutagenic 9-(4'-aminophenyl)-9H-pyrido[3,4-b]indole (aminophenylnorharman, APNH), formed from norharman and aniline in the presence of S9 mix, is thought to be accountable for the co-mutagenic action of norharman. Our previous studies suggest that cytochrome P-450s (CYPs) are involved in the generation of APNH. In order to identify the responsible CYP species in the present study, norharman (8 mg) and aniline (4 mg) were incubated with individual recombinant human CYPs (2 nmol) at 37 degrees C for 20 min. Formation of APNH was observed with CYP1A1, CYP1A2, CYP1B1, CYP2B6, CYP2D6, CYP2E1 and CYP3A4, but not with CYP2A6, CYP2C9 and CYP2C19. The amounts of APNH from norharman and aniline were 33 ng for CYP1A1, 15 ng for CYP3A4, 7 ng for CYP2D6, 6 ng for CYP1A2 and 5 ng for CYP2B6. APNH formation in the presence of CYP1B1 and CYP2E1 was very low at around one fiftieth of that with CYP3A4. When CYP selective chemical inhibitors, such as furafylline for CYP1A2 and ketoconazole for CYP3A4, were added to the reaction mixture of norharman, aniline and human microsomes, formation of APNH was decreased to 14 and 16% of the control level, respectively. Moreover, human lung microsomes also showed the activity of APNH formation from norharman and aniline, albeit at only one hundredth of that with liver microsomes. In general, content in human liver microsomes is rather high for CYP3A4 and CYP1A2 but relatively low for CYP2D6 and CYP2B6, at about 30, 10, 1.5% and less than 1% of the total CYP, respectively. Although CYP1A1 showed the highest APNH formation activity, its expression in human liver is reported to be below the level of detection. Based on these observations, it is suggested that the practical major contributors to the formation of APNH from norharman and aniline are CYP3A4 and CYP1A2, the responsible reactions mainly occurring in the liver.
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PMID:Identification of cytochrome P-450s involved in the formation of APNH from norharman with aniline. 1527 27

Green tea extract is a widely used dietary supplement. The objective of this study was to assess the influence of a decaffeinated green tea (DGT; Camellia sinensis) extract on the activity of the drug-metabolizing enzymes cytochrome P-450 2D6 and 3A4. Probe drugs dextromethorphan (30 mg, CYP2D6 activity) and alprazolam (ALPZ; 2 mg, CYP3A4 activity) were administered orally to healthy volunteers (n = 11) at baseline, and again after treatment with four DGT capsules/day for 14 days. Each DGT capsule contained 211 +/- 25 mg of green tea catechins and <1 mg of caffeine. Dextromethorphan metabolic ratios (DMRs) and alprazolam pharmacokinetics were determined at baseline and after DGT treatment. There were no significant differences in ALPZ pharmacokinetics at baseline and after DGT treatment (all P values >/= 0.05; maximum concentration in plasma, 33 +/- 8 versus 34 +/- 13 ng/ml; time to reach maximum concentration in plasma, 1.4 +/- 1.2 versus 1.4 +/- 1.2 h; area under the plasma concentration versus time curve, 480 +/- 119 versus 510 +/- 107 h. ng. ml(-1); half-life of elimination, 12.3 +/- 1.7 versus 13.1 +/- 3.4 h). The DMR was 0.053 +/- 0.045 at baseline and 0.041 +/- 0.032 after DGT supplementation (P > 0.05). The plasma concentration of the green tea flavonoid, (-)-epigallocatechin gallate, reached 1.3 +/- 1.8 microM 2 h after DGT treatment. Our results indicate that DGT is unlikely to alter the disposition of medications primarily dependent on the CYP2D6 or CYP3A4 pathways of metabolism.
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PMID:Green tea (Camellia sinensis) extract does not alter cytochrome p450 3A4 or 2D6 activity in healthy volunteers. 1531 29

Artemether is an efficacious antimalarial drug that also displays antischistosomal properties. Grapefruit juice increases the oral availability of a variety of the CYP3A4 substrates. This study was designed to evaluate the effect of repeated administration of grapefruit juice with artemether on the hepatic activities of cytochrome P-450 (CYP450) and cytochrome b5 (cyt b5), on the serum levels of some biochemical enzymes and antischistosome efficacy. Results showed that administration of grapefruit juice alone induced more inhibition in the hepatic activities of CYP450 and cyt b5 than that produced by Schistosoma mansoni infection. Moreover, it enhanced degeneration of eggs and accelerated healing of the pathological granulomatous lesions. Treatment of S. mansoni-infected mice with artemether at a total dose of 300 mg/kg resulted in total and female worm burden reductions of 66.7 and 90.1%, respectively, hence protecting the host from damage induced by schistosome eggs. Treatment of S. mansoni-infected mice with artemether at 150 mg/kg reduced the total and female worm numbers by 43.3 and 54.4%, respectively, thus somewhat ameliorating hepatic granulomatous lesions compared with the infected untreated group. This was associated with no change in the hepatic activities of CYP450 and cyt b5 and in the serum levels of total protein, albumin, globulin and alanine aminotransferase compared with the uninfected control group. Coadministration of grapefruit juice with the lower dose (150 mg/kg) of artemether eliminated eggs and granulomatous reactions. In this group, the inhibitory effects of grapefruit juice on CYP450 and cyt b5 were apparent but serum liver enzymes were unchanged compared with the uninfected control group. Coadministration of grapefruit juice with artemether achieved complete protection of the host from damage induced by schistosomal infection.
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PMID:Effect of artemether alone and in combination with grapefruit juice on hepatic drug-metabolising enzymes and biochemical aspects in experimental Schistosoma mansoni. 1554 1

The participation of cytochrome P-450 (CYP) isoforms in the metabolism of selegiline was investigated. Experiments using recombinant CYP isoforms expressed in human lymphoblastoid cells showed CYP2B6 to be the major CYP isoform involved with the metabolism of selegiline. CYP1A2 and CYP3A4 also contributed to the metabolism of selegiline but their catalytic activities were much less than that of CYP2B6. CYP2B6 had a higher affinity for both N-depropagylation (K(m)=21.4 microM) and N-demethylation (K(m)=25.2 microM) of selegiline than CYP3A4 and CYP1A2. In immunoinhibition studies using mixed human hepatic microsomes, selegiline N-depropagylation activity was most strongly inhibited by anti-CYP2B and anti-CYP3A antibodies, while selegiline N-demethylation activity was most inhibited by anti-CYP2B antibody. In CYP2B6-rich human hepatic microsomes, anti-CYP2B antibody had the strongest inhibitory effects on both activities. Selegiline inhibited CYP2B6-mediated (S)-mephenytoin N-demethylation activity and CYP2C19-mediated (S)-mephenytoin 4'-hydroxylation activity. These findings suggest that attention should be paid to the drug-drug interaction associated with CYP2B6 and CYP2C19. In conclusion, CYP2B6 participates in the metabolism of selegiline but the degree of its contribution varies with the level of its expression in human liver.
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PMID:Metabolism of selegiline hydrochloride, a selective monoamine b-type inhibitor, in human liver microsomes. 1561 70

Cytotoxicity and apoptosis are common problems in the isolation and storage of human hepatocytes. In vitro environments of hepatocytes during cell infusion may be critical to reducing cellular damage and enhancing cell viability. We examined the effects of donor liver histology (40-50% steatosis vs. normal), incubation time, temperature, and three solutions for infusion on banked primary human hepatocytes, by studying: trypan blue exclusion, AST release, LDH release, MTT assay, detection of DNA ladder, and a hepatocyte proliferation assay. In addition, the microstructure functions of the endoplasmic reticulum and mitochondria of the intact hepatocytes were determined by measuring correlates of UGT 1A1 and cytochrome P-450 3A (CYP3A4) activity. In general, hepatocyte viability decreased significantly within 60 min after thawing. Cells suspended in 5% dextrose lactated Ringers solution (D5LR) maintained greater cell viability. Hepatocytes from normal liver donors showed less AST and LDH enzyme leak in comparison with cells from fatty liver donors. Mild hypothermic temperature (32 degrees C) inhibited cellular damage that otherwise significantly increased at 60 min. Hepatocytes did not proliferate until 12 h from thaw, regardless of supernatant or conditions of suspension. CYP3A4 activity and a marker for UGT 1A1 activity in hepatocytes from normal donor livers were higher than those from steatotic donor livers. These findings suggest that hepatocytes suspended for infusion after isolation from normal liver donors have normal biological functions and less cellular damage/necrosis in contrast with those isolated from fatty liver donors. These damages are inhibited significantly by maintaining hepatocytes at a mild hypothermic temperature (32 degrees C). D5LR alone maintained the best cell viability for up to 60 min. Media of D5LR + adenosine and HMM were able to partially inhibit hepatocyte apoptosis in hepatocytes from steatotic livers.
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PMID:Optimization of conditions for clinical human hepatocyte infusion. 1564 38

Recent studies have revealed that pregnane X receptor (PXR) can function as a master regulator to control the expression of phase I and phase II drug-metabolizing enzymes, as well as members of the drug transporter family, including multiple drug resistance (MDR) 1, which has a major role in multidrug resistance. Previously, we have demonstrated that steroid/xenobiotics metabolism by tumor tissue through the PXR-cytochrome P-450 3A (CYP3A) pathway might play an important role in endometrial cancer. In this study, we examined which endocrine-disrupting chemicals (EDCs) and anticancer agents might be ligands for PXR and whether these chemicals enhanced PXR-mediated transcription through two different PXR-responsive elements (PXREs), CYP3A4 and MDR1, in endometrial cancer cell lines. Some steroids/EDCs strongly activated PXR-mediated transcription through the CYP3A4-responsive element compared with the MDR1-responsive element, whereas these steroids/EDCs also enhanced the CYP3A4 expression compared with the MDR1 expression. In contrast, the anticancer agents, cisplatin and paclitaxel, strongly activated PXR-mediated transcription through the MDR1-responsive element compared with the CYP3A4-responsive element, whereas these drugs also enhanced the MDR1 expression compared with the CYP3A4 expression. We also analyzed how these ligands regulated PXR-mediated transcription through two different PXREs. In the presence of PXR ligands, there was no difference in the DNA binding affinity of the PXR/retinoid X receptor heterodimer to each PXRE, but there were different interactions of the coactivator to each PXR/PXRE complex. These data suggested that PXR ligands enhanced PXR-mediated transcription in a ligand- and promoter-dependent fashion, which in turn differentially regulated the expression of individual PXR targets, especially CYP3A4 and MDR1.
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PMID:The pregnane X receptor regulates gene expression in a ligand- and promoter-selective fashion. 1565 19

The effects of modified cyclodextrins (CDs) hydroxypropyl-beta-CD and methyl-beta-CD were studied in vitro on cDNA-expressed human cytochrome P-450 (CYP) activities (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). The modified CDs inhibited the activities of CYP2C19 and CYP3A4 while enhancing CYP2C9 activity by 140 to 176% relative to the control values at lower concentrations. In addition, methyl-beta-CD inhibited CYP1A2 and CYP2D6 at higher concentrations.
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PMID:Interaction of modified cyclodextrins with cytochrome P-450. 1566 98

We evaluated the pharmacokinetic interaction between a low-hyperforin St John's wort (SJW) extract and alprazolam, caffeine, tolbutamide, and digoxin. Previous reports on other SJW products had shown remarkably decreased plasma concentrations of certain co-medicated drugs, which was attributed to an inducing effect of SJW on cytochrome P-450 (CYP) and p-glycoprotein (p-gp) activity. Two randomised, placebo-controlled studies were performed with 28 healthy volunteers (age 18 - 55 years) in each study. In study A, single doses of alprazolam (1 mg; substrate of CYP3A4) and caffeine (100 mg; CYP1A2) were given on days 1 and 11. In study B, single doses of tolbutamide (500 mg, days 1 and 11; CYP2C9) and multiple doses of digoxin (0.75 mg on days -2 and -1, 0.25 mg/die on days 1 to 11; p-gp) were given. The participants received SJW (Esbericum capsules; 240 mg/die of extract, 3.5 mg hyperforin) or placebo on days 2 to 11. Blood for pharmacokinetic analysis was drawn on days 1 and 11. No statistically significant differences were found in the primary kinetic parameter, AUC0 - 24, of alprazolam, caffeine (AUC0 - 12), paraxanthine, tolbutamide, 4-hydroxytolbutamide, and digoxin between the placebo group and the SJW group at the end of the study. The SJW-induced change in AUCs was less than 12 % of the initial median AUC of the participants in studies A and B, thus clinically irrelevant. On day 11, trough concentrations were 2.0 (range 0.6 - 4.1) microg/L and 1.0 (0.2 - 3.9) microg/L for hypericin and pseudohypericin, respectively, whereas hyperforin concentrations were below the quantification limit (< 1 microg/L). Kinetics of investigated probe drugs were only marginally influenced by concomitant treatment with Esbericum capsules. This may be due in particular to the low hyperforin plasma concentration as this SJW component has been shown to activate the PXR receptor which regulates expression of CYP3A4 and p-gp. Our findings corroborate the view that reports about interactions of other SJW extracts seem not to be predictive for the product we studied.
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PMID:No relevant interaction with alprazolam, caffeine, tolbutamide, and digoxin by treatment with a low-hyperforin St John's wort extract. 1585 9

This report documents the occurrence of torsades de pointes (TdP) caused by marked QT interval prolongation in the case of a 71-year-old woman receiving both metronidazole and amiodarone for the treatment of pseudomembranous colitis and paroxysmal atrial fibrillation. The case highlights a previously unknown drug interaction. The role of inhibition of cytochrome P-450 CYP3A4 is discussed.
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PMID:QT interval prolongation and torsades de pointes due to a coadministration of metronidazole and amiodarone. 1586 86

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