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Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
CYP2E1 metabolizes both endogenous substrates, such as ethanol, acetone, and acetal, and exogenous substrates including benzene, carbon tetrachloride, ethylene glycol, and nitrosamines, which are premutagens found in cigarette smoke. It is an ethanol-oxidizing enzyme that is involved in the metabolism of many low-molecular-weight xenobiotics including acetaminophen, benzene, and chlorzoxazone, as well as halothane (Koop 1992; Lieber 1997). Chlorzoxazone 6-hydroxylation has been shown to be catalyzed specifically by CYP2E1. Chlorzoxazone assay is used to estimate CYP2E1 activity in vivo noninvasively (O’Shea et al. 1994). CYP2E1 also catalyzes the 11-hydroxylation of lauric acid as well as oxidizes indole via 3-hydroxylation. Many studies have shown that 2E1 is involved in oxidizing of low-molecular-weight potential carcinogens such as nitrosamines, benzene, styrene, CCl4, CHCl3, CH2Cl2, CH3CCl3, 1,2-dichloropropane, ethylene dichloride, ethylene dibromide, vinyl bromide, acrylonitrile, vinyl carbamate, ethyl carbamate, and trichloroethylene (Hoffler et al. 2003; H. Wang et al. 2002).
Main Classes of Drugs
Published in Jerome Z. Litt, Neil H. Shear, Litt's Drug Eruption & Reaction Manual, 2017
Central muscle relaxantCarisoprodolChlormezanoneChlorzoxazoneCyclobenzaprineMeprobamateMetaxaloneMethocarbamolOrphenadrine
The Myofascial Pain Syndrome
Published in Gary W. Jay, Practical Guide to Chronic Pain Syndromes, 2016
Muscle relaxants, also covered in detail in chapter 2, may be used, and include, for acute muscle spasm CarisoprodolChlorzoxazoneMetaxaloneMethocarbamolOrphenadrine
The alteration of drug metabolism enzymes and pharmacokinetic parameters in nonalcoholic fatty liver disease: current animal models and clinical practice
Published in Drug Metabolism Reviews, 2023
Yan Zhu, Li Chen, Yuqi He, Lin Qin, Daopeng Tan, Zhaojun Bai, Yu Song, Yu-He Wang
Chlorzoxazone is a centrally-acting agent for painful musculoskeletal conditions (Nielsen et al. 2016), and it is a selective probe of CYP2E1 activity in vivo. It was found that the metabolic clearance of chlorzoxazone was markedly elevated in obese subjects with NASH than those without NASH (Emery et al. 2003). Midazolam is a short-acting benzodiazepine that is widely used as a premedicant prior to surgery, for induction of anesthesia, and for conscious sedation (Rodolà 2006). The CYP3A4 protein expression levels were significantly lower in patients with NAFLD and NASH. Compared with control subjects, midazolam concentrations were significantly higher in human subjects with NASH (Woolsey et al. 2015; Jamwal et al. 2018). In the HFD-fed mice model, both mRNA and protein expression levels of Cyp3a11/CYP3A4 tended to decrease. What’s more, HFD mice had significantly prolonged sleeping times after midazolam (Cyp3a11/CYP3A4 substrate) (Ghose et al. 2011). The results led us to wonder whether current drug dosage recommendations may need to be reevaluated in the NAFLD population to ensure the premier clinical outcomes of these drug therapies.
Subacute oral toxicology and toxicokinetics of pterostilbene, a novel Top1/Tdp1 inhibiting anti-tumor reagent
Published in Drug and Chemical Toxicology, 2023
Changcheng Sun, Ying Li, Yutian Zhang, Haoyan Huang, Huili Chen, Jiaqin Chen, Luyao Han, Xiang Chen, Xijing Chen, Yongjie Zhang
In order to ensure the stability and reliability of the analysis method, validation was performed to determine specificity, standard curve, and linear range, the lower limit of quantification (LLOQ), precision and accuracy, extraction recovery, matrix effect, and stability for the established UPLC–MS/MS method. The method was validated in compliance with the European Medicines Agency (EMA) guidelines. Specificity results showed no interferences at the retention of analytes from six different-sourced blank plasma, which met the requirements of sample determination. Calibration curve of pterostilbene exhibited good linearity in the range from 10 to 10 000 ng/mL, with a representative equation of y = 0.00939x + 0.00819 (R2>0.99). LLOQ, quality control low (QCL), quality control medium (QCM), and quality control high (QCH) accuracies were between 90% and 110%, and the CV values were less than 10%, which met the requirements for biological sample determination. The matrix effect and extraction recovery of pterostilbene in plasma samples also met the requirements. The results showed that there was no evident matrix effect in the determination of samples. The recovery rate of pterostilbene was (101.60 ± 1.16)% to (102.51 ± 2.33)%. The recovery rate of chlorzoxazone was (102.5 ± 1.58)%. The stability of the working solution at room temperature and 4 °C for 4 h and 24 h was acceptable.
Evaluation of the effect of Bovis Calculus Artifactus on eight rat liver cytochrome P450 isozymes using LC-MS/MS and cocktail approach
Published in Xenobiotica, 2021
Yun-Jing Zhang, Wen-Li Zhou, Fei Yu, Qian Wang, Can Peng, Jia-Yi Kan
The simultaneous incubation of substrates may lead to substrate interactions and inhibition of CYP activity by the solvent. So we used the concentrations of the substrates below their respective Michaelis constants to minimize the interactions and used organic solvents at low concentration (<1% (volume/volume)). Phenacetin had no effect on the metabolism of other probe drugs when it was lower than 152 μM. In this experiment, the concentration of phenacetin was 150 μM. Bupropion is the preferred probe drug for CYP2B6 and has been used in many cocktail methods and has no effect on the activities of other isozymes when less than 100 μM. According to the Km value of bupropion (67–168 μM), the concentration of bupropion is selected to be 95 μM, and 2.4 μM for amodiaquine (Km values: 2.6 μM). For tolbutamide, the concentration was set at 109 μM (Km values: 67–838 μM). The concentration of S-mephenytoin was set at 50 μM according to the Km value of (78 μM). As probe drug of CYP2D6, dextromethorphan has no effect on other probe drugs when the concentration is lower than 25 μM. In this study, the concentration of dextromethorphan is 10 μM. Midazolam was selected as a CYP3A4 probe drug with a concentration of 32 μM. When the concentration of chlorzoxazone is less than 50 μM, it has no effect on other subtypes of enzymes. In this experiment, the concentration of chlorzoxazone is 15 μM (Xia et al. 2021; Yang et al. 2014).