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He E. Kang - One of the best experts on this subject based on the ideXlab platform.
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Interaction between udenafil and tamsulosin in rats: non-competitive inhibition of tamsulosin metabolism by udenafil via hepatic CYP3A1/2
British Journal of Pharmacology, 2009Co-Authors: He E. KangAbstract:Background and purpose: Orthostatic hypotension has been observed when PDE 5 (cGMP-specific phosphodiesterase type 5) inhibitors are co-administered with α-adrenoceptor antagonists. Here we assessed the pharmacokinetic and haemodynamic interactions between udenafil and tamsulosin in rats, as both drugs are metabolized via rat hepatic Cytochrome P450 3A1/2. Experimental approach: Interactions between the two drugs were evaluated in rats after simultaneous 1 or 15 min i.v. infusion or after p.o. administration of udenafil (30 mg·kg−1) and/or tamsulosin (1 mg·kg−1). In vitro metabolism of tamsulosin with udenafil was measured to obtain the inhibition constant (Ki) and [I]/Ki ratio of udenafil. Key results: The total area under the plasma concentration–time curve from time zero to time infinity (AUC)s (or AUC0–4h) of tamsulosin were significantly greater after 15 min of i.v. infusion or after oral administration with udenafil, compared with tamsulosin alone. The hepatic first-pass metabolism of tamsulosin was inhibited by udenafil, and the inhibition in vitro was in a non-competitive mode. The arterial systolic blood pressure was significantly lower at 5, 10 and 60 min after oral co-administration of the drugs. Conclusions and implications: The significantly greater AUC of tamsulosin after i.v. and p.o. administration of both drugs may be attributable to non-competitive inhibition of Cytochrome P450 3A1/2-mediated hepatic tamsulosin metabolism by udenafil. The inhibition was also observed in human liver S9 fractions, suggesting that a reassessment of the oral dosage of tamsulosin is necessary when udenafil and tamsulosin are co-administered to patients with benign prostatic hyperplasia.
Lin Xie - One of the best experts on this subject based on the ideXlab platform.
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herb drug interactions in vivo and in vitro effect of shenmai injection a herbal preparation on the metabolic activities of hepatic Cytochrome P450 3A1 2 2c6 1a2 and 2e1 in rats
Planta Medica, 2010Co-Authors: Chunhua Xia, Jianguo Sun, Guangji Wang, Lili Shang, Xiaoxuan Zhang, Rong Zhang, Ying Peng, Xiaojin Wang, Haiping Hao, Lin XieAbstract:Shenmai injection (SMI), a mixture of Radix Ginseng and Radix Ophiopogonis, is one of the most popular herbal medicinal products and is widely used for the treatment of coronary atherosclerotic cardiopathy and viral myocarditis. The purpose of this study was to investigate the effect of SMI, in vivo and in vitro, on the metabolic activities of hepatic Cytochrome CYP450 3A1/2, 2C6, 2E1, and 1A2 in rats. After a single or multiple pretreatment with SMI, the rats were administrated intravenously a cocktail containing midazolam (1 mg/kg), diclofenac (0.5 mg/kg), theophylline (1 mg/kg), and chlorzoxazone (0.5 mg/kg) as probe substrates of rat CYP450 3A1/2, 2C6, 1A2, and 2E1, respectively. Single and multiple SMI pretreatment to rats resulted in a rise of 33.8 % (p < 0.01) and 25.6 % (p < 0.01) in AUC for midazolam, and an increase in AUC for diclofenac by 14.7 % (p < 0.05) and 31.2 % (p < 0.01), respectively. However, the pharmacokinetics of chlorzoxazone and theophylline in rats was not altered markedly. In rat liver microsomes, linear mixed-type inhibition of SMI against the enzyme activities of CYP3A1/2, CYP2C6, and CYP1A2 was shown with IC(50) values of 3.3 %, 2.0 %, and 3.1 % and K(i) values of 3.8 %, 1.5 %. and 1.9 %, respectively. These in vivo and in vitro results demonstrated that SMI had the potential to inhibit the activities of hepatic CYP3A1/2 and CYP2C6, but might not significantly affect CYP1A2 and CYP2E1-mediated metabolism in rats.
Xijing Chen - One of the best experts on this subject based on the ideXlab platform.
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effect of triacontanol on the pharmacokinetics of docetaxel in rats associated with induction of Cytochrome P450 3A1 2
Xenobiotica, 2014Co-Authors: Shuhua Deng, Cuiyun Li, Qiuyang Zhang, Chunfeng Wang, Di Zhao, Yongjie Zhang, Wei Zhang, Ning Li, Xijing ChenAbstract:Abstract1. Triacontanol was confirmed to have a potential anti-cancer effect, the aim was to assess whether the co-administration of triacontanol alters the exposure of docetaxel via inducing hepatic CYP3A1/2 activity. The concentration of docetaxel in rats pretreated with triacontanol for seven successive days was determined, and the expression levels of CYP3A protein and mRNA were analyzed by the western blot and real time polymerase chain reaction (RT-PCR) technique, respectively.2. The concentrations of docetaxel in rats pretreated with triacontanol were decreased, with 61.5%, 61.9% decrease in AUC0–24h and 65.7%, 54.9% reduction in Cmax (120 and 180 mg kg−1, respectively) compared with the control. Hepatic clearance of docetaxel was enhanced in vitro and in vivo at dosage of 120 and 180 mg kg−1, and CYP3A activity was up-regulated by measuring the formation rate of 1-hydroxymidazolam. Triacontanol preferentially induced protein expression level of CYP3A2 in a dose-dependent manner and of CYP 3A1 at d...
Xin Wang - One of the best experts on this subject based on the ideXlab platform.
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crispr knockout rat Cytochrome P450 3A1 2 model for advancing drug metabolism and pharmacokinetics research
Scientific Reports, 2017Co-Authors: Yanjiao Shao, Xuan Qin, Mingyao Liu, Ang Chen, Daozhi Liu, Xin WangAbstract:Cytochrome P450 (CYP) 3A accounts for nearly 30% of the total CYP enzymes in the human liver and participates in the metabolism of over 50% of clinical drugs. Moreover, CYP3A plays an important role in chemical metabolism, toxicity, and carcinogenicity. New animal models are needed to investigate CYP3A functions, especially for drug metabolism. In this report, Cyp3A1/2 double knockout (KO) rats were generated by CRISPR-Cas9 technology, and then were characterized for viability and physiological status. The Cyp3A1/2 double KO rats were viable and fertile, and had no obvious physiological abnormities. Compared with the wild-type (WT) rat, Cyp3A1/2 expression was completely absent in the liver of the KO rat. In vitro and in vivo metabolic studies of the CYP3A1/2 substrates indicated that CYP3A1/2 was functionally inactive in double KO rats. The Cyp3A1/2 double KO rat model was successfully generated and characterized. The Cyp3A1/2 KO rats are a novel rodent animal model that will be a powerful tool for the study of the physiological and pharmacological roles of CYP3A, especially in drug and chemical metabolism in vivo.
Paul E Thomas - One of the best experts on this subject based on the ideXlab platform.
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differential regulation of Cytochrome P450 3A1 and P450 3a2 in rat liver following dexamethasone treatment
Journal of Biochemical Toxicology, 1995Co-Authors: Supratim Choudhuri, Xu Jie Zhang, Mark J Waskiewicz, Paul E ThomasAbstract:Induction of P450 3A1 and P450 3A2 was studied in adult rat liver following treatment with a single high dose of dexamethasone (DEX). The increase of both P450 3A1 and 3A2 occurred at the level of mRNA as well as protein. P450 3A isozymes thus induced were catalytically active. No constitutive expression of P450 3A1 mRNA or protein was observed in males or females. Constitutive expression of P450 3A2 mRNA and protein was observed in males but not in females. Additionally, in females, P450 3A2 was almost nondetectable compared to that in males, at any dose of DEX. A time course study following DEX treatment showed that P450 3A1 mRNA and protein were detectable in both sexes at 12 hours, increased until 48 hours, and then declined. The decline was more rapid in males. P450 3A2 mRNA and protein increased as early as 3 hours, increased further up to 48 hours, and slowly declined thereafter. A dose-response study indicated that P450 3A1 mRNA and protein progressively increased in both sexes from a dose of 30 mg/kg. In contrast, P450 3A2 mRNA and protein in males did not increase up to a dose of 30 mg/kg but increased at higher doses. Total P450 content and P450 3A catalytic activity were also found to increase with time and dose. © 1996 John Wiley & Sons, Inc.
