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Microsomal Cytochrome P450 (microsomal + cytochrome_p450)
Selected AbstractsEffects of cysteine on metformin pharmacokinetics in rats with protein-calorie malnutrition: partial restoration of some parameters to control levelsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2008Young H. Choi Metformin is metabolized primarily via hepatic microsomal cytochrome P450 (CYP)2C11, CYP2D1 and CYP3A1/2 in rats. The expression and mRNA levels of hepatic CYP2C11 and CYP3A1/2 are decreased in rats with protein-calorie malnutrition (PCM), but these levels are fully or partially restored to control levels in PMC rats by oral cysteine supplementation (PCMC rats). Thus, it would be expected that the pharmacokinetic parameters of metformin in PCM rats would be returned to control levels in PCMC rats. Metformin was administered i.v. (100 mg kg,1) and orally (100 mg kg,1) to control, CC (control rats with oral cysteine supplementation), PCM and PCMC rats. The following pharmacokinetic parameters of metformin following i.v. administration were restored from levels in PCM rats to levels in control rats in PCMC rats: intrinsic clearance (0.0350, 0.0309, 0.0253 and 0.0316 mL min,1 mg,1 protein for control, CC, PCM, and PCMC rats, respectively), total area under the plasma concentration-time curve from time zero to time infinity (AUC; 4110, 4290, 5540 and 4430 ,g min mL,1, respectively), and time-averaged non-renal clearance (8.12, 7.95, 5.94 and 8.17 mL min,1 kg,1, respectively). AUC values following oral administration were comparable between control and PCMC rats (1520, 1480, 2290 and 1680 ,g min mL,1, respectively). [source] Interaction of Drugs and Chinese Herbs: Pharmacokinetic Changes of Tolbutamide and Diazepam Caused by Extract of Angelica dahuricaJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 8 2000KAZUHISA ISHIHARA The inhibitory effects of Angelica dahurica root extract on rat liver microsomal cytochrome P450 and drug-drug interactions were studied. The 2,- and 16,-hydroxylase activity of testosterone were most strongly inhibited, with 17.2% and 28.5% of their activity remaining, respectively, after oral administration of A. dahurica extract at a 1 g kg,1 dose. 6,-Hydroxylase activity was also inhibited, with 70% of its activity remaining, under the same conditions. In addition, treatment with the extract inhibited the metabolism of tolbutamide, nifedipine and bufuralol. These results showed that the extract inhibited the various isoforms of cytochrome P450 such as CYP2C, CYP3A and CYP2D1. The A. dahurica extract delayed elimination of tolbutamide after intravenous administration at a 10 mg kg,1 dose to rats. Thus, the extract altered the liver intrinsic clearance. It had little effect, however, on the pharmacokinetic parameters of diazepam after intravenous administration at 10 mg kg,1. Since diazepam showed high clearance, it underwent hepatic blood flow rate-limited metabolism. Therefore, the change of intrinsic clearance had little effect on hepatic clearance. However, the Cmax value after oral administration of diazepam with extract treatment was four times that with non-treatment. It was suggested that the first-pass effect was changed markedly by the extract. High-dose (1 g kg,1), but not low dose (0.3 g kg,1), administration of A. dahurica extract increased significantly the duration of rotarod disruption following intravenous administration of diazepam at 5 mg kg,1. It was concluded that administration of A. dahurica extract has the potential to interfere with the metabolism, by liver cytochrome P450, of other drugs. [source] Effects of cysteine on the pharmacokinetics of itraconazole in rats with protein-calorie malnutritionBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 2 2003Ae K. Lee Abstract The effects of cysteine on the pharmacokinetics of itraconazole were investigated after intravenous, 20 mg/kg, and oral, 50 mg/kg, administration of the drug to control rats (fed for 4 weeks on 23% casein diet) and rats with PCM (protein-calorie malnutrition, fed for 4 weeks on 5% casein diet) and PCMC (PCM with oral cysteine supplementation, 250 mg/kg, twice daily during the fourth week). After intravenous administration of itraconazole to rats with PCM, the area under the plasma concentration,time curve from time zero to time infinity (AUC) of itraconazole was significantly greater (3580 compared with 2670 and 2980 µg min/ml) than those in control rats and rats with PCMC (the values between control rats and rats with PCMC were not significantly different). The above data suggested that metabolism of itraconazole decreased significantly in rats with PCM due to suppression of hepatic microsomal cytochrome P450 (CYP) 3A23 in the rats. The results could be expected since in rats with PCM, the level of CYP3A23 decreased significantly as compared to control. Itraconazole was reported to be metabolized via CYP3A4 to several metabolites, including hydroxyitraconazole, in human subjects. Human CYP3A4 and rat CYP3A1 (CYP3A23) proteins have 73% homology. By cysteine supplementation (rats with PCMC), the AUC of itraconazole was restored fully to control levels. Copyright © 2003 John Wiley & Sons, Ltd. [source] Cloning, purification, crystallization and preliminary X-ray analysis of a chimeric NADPH-cytochrome P450 reductaseACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 3 2009Louise Aigrain NADPH-cytochrome P450 reductase (CPR) is the favoured redox partner of microsomal cytochromes P450. This protein is composed of two flavin-containing domains (FMN and FAD) connected by a structured linker. An active CPR chimera consisting of the yeast FMN and human FAD domains has been produced, purified and crystallized. The crystals belonged to the monoclinic space group C2 and contained one molecule per asymmetric unit. Molecular replacement was performed using the published rat and yeast structures as search models. The initial electron-density maps revealed that the chimeric enzyme had crystallized in a conformation that differed from those of previously solved structures. [source] RNA-Interference Approach to Study Functions of NADPH,:,Cytochrome P450 Oxidoreductase in Human HepatocytesCHEMISTRY & BIODIVERSITY, Issue 11 2009Diana Abstract Human NADPH,:,cytochrome P450 oxidoreductase (POR) is encoded by a single gene on chromosome 7q11.2. This flavoprotein donates electrons derived from NADPH to a variety of acceptor proteins, including squalene monooxygenase, heme oxygenase, cytochrome b5, and many microsomal cytochromes P450 (CYPs), which are involved in oxidative drug metabolism, steroidogenesis, and other functions. Numerous aspects related to cellular POR expression have not been systematically investigated. Interestingly, POR expression is lower compared to CYPs and may thus be limiting for monooxygenase activities, but conversely, POR knock-out in mice resulted in compensatory upregulation of CYPs. POR may also influence intracellular cholesterol and lipid homeostasis. To systematically investigate such effects, we developed specific POR gene silencing in cell lines and primary human hepatocytes by RNA interference using small interfering RNAs (siRNAs). In HepG2 cells, POR mRNA could be reduced by 95% over 4 days accompanied by reduced protein content and activity. In primary human hepatocytes, POR mRNA knock-down was less effective and more variable. Analysis of CYPs indicated induction of CYP3A4 but not CYP1A2 or CYP2D6. These results demonstrate that POR can be efficiently and almost completely silenced in HepG2 cells and, at least partially, in primary human hepatocytes. This will allow systematic studies of various consequences of POR variability in human cells. [source] | |||||||||||||