Dataset Information

In silico ADME and Toxicity Prediction of Ceftazidime and Its Impurities.

ABSTRACT: To improve the quality control of drugs, we predicted the absorption, distribution, metabolism, excretion, and toxicity (ADMET) of ceftazidime (CAZ) and its impurities via in silico methods. We used three types of quantitative structure-activity relationship and docking software for precise prediction: Discovery Studio 4.0, OECD QSAR Toolbox 4.1, Toxtree, and the pkCSM approach. The pharmacokinetics and toxicity of ceftazidime and impurity A (?-2-CAZ) are similar. The biological properties of impurity B (CAZ E-isomer) are different from CAZ. Therefore, we focused on drug stability to analyze impurity B. Impurities D and I have strong lipophilicity, good intestinal absorption, and poor excretion in the body. Impurity D is particularly neurotoxic and genotoxic. It is important to control the content of impurity D. The toxicity of impurity F is low, but the toxicity is enhanced when it becomes the C-3 side chain of CAZ and forms a quaternary amine group. We conclude that the beta-lactam ring of nucleus, the quaternary amine group at the C-3 side chain, and the acetates at the C-7 side chain of CAZ are the main toxic functional groups. Impurities B and D may be the genetic impurity in CAZ and may also have neurotoxicity. This in silico approach can predict the toxicity of other cephalosporins and impurities.

SUBMITTER: Han Y

PROVIDER: S-EPMC6491819 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

<i>In silico</i> ADME and Toxicity Prediction of Ceftazidime and Its Impurities.

Han Ying Y Zhang Jingpu J Hu Chang Qin CQ Zhang Xia X Ma Bufang B Zhang Peipei P

Frontiers in pharmacology 20190424

To improve the quality control of drugs, we predicted the absorption, distribution, metabolism, excretion, and toxicity (ADMET) of ceftazidime (CAZ) and its impurities via <i>in silico</i> methods. We used three types of quantitative structure-activity relationship and docking software for precise prediction: Discovery Studio 4.0, OECD QSAR Toolbox 4.1, Toxtree, and the pkCSM approach. The pharmacokinetics and toxicity of ceftazidime and impurity A (Δ-2-CAZ) are similar. The biological propertie ...[more]

PMID: 31068821

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Project description:Zearalenone (ZEA), α-zearalenol (α-ZEL) and β-zearalenol (β-ZEL) (ZEA's metabolites) are co/present in cereals, fruits or their products. All three with other compounds, constitute a cocktail-mixture that consumers (and also animals) are exposed and never entirely evaluated, nor in vitro nor in vivo. Effect of ZEA has been correlated to endocrine disruptor alterations as well as its metabolites (α-ZEL and β-ZEL); however, toxic effects associated to metabolites generated once ingested are unknown and difficult to study. The present study defines the metabolomics profile of all three mycotoxins (ZEA, α-ZEL and β-ZEL) and explores the prediction of their toxic effects proposing an in silico workflow by using three programs of predictions: MetaTox, SwissADME and PASS online. Metabolomic profile was also defined and toxic effect evaluated for all metabolite products from Phase I and II reaction (a total of 15 compounds). Results revealed that products describing metabolomics profile were: from O-glucuronidation (1z and 2z for ZEA and 1 ab, 2 ab and 3 ab for ZEA's metabolites), S-sulfation (3z and 4z for ZEA and 4 ab, 5 ab and 6 ab for ZEA's metabolites) and hydrolysis (5z and 7 ab for ZEA's metabolites, respectively). Lipinsky's rule-of-five was followed by all compounds except those coming from O-glucuronidation (HBA>10). Metabolite products had better properties to reach blood brain barrier than initial mycotoxins. According to Pa values (probability of activation) order of toxic effects studied was carcinogenicity > nephrotoxic > hepatotoxic > endocrine disruptor > mutagenic (AMES TEST) > genotoxic. Prediction of inhibition, induction and substrate function on different isoforms of Cytochrome P450 (CYP1A1, CYP1A2, CYP2C9 and CYP3A4) varied for each compounds analyzed; similarly, for activation of caspases 3 and 8. Relying to our findings, the metabolomics profile of ZEA, α-ZEL and β-ZEL analyzed by in silico programs predicts alteration of systems/pathways/mechanisms that ends up causing several toxic effects, giving an excellent sight and direct studies before starting in vitro or in vivo assays contributing to 3Rs principle; however, confirmation can be only demonstrated by performing those assays.

Dataset Information

In silico ADME and Toxicity Prediction of Ceftazidime and Its Impurities.

Publications

<i>In silico</i> ADME and Toxicity Prediction of Ceftazidime and Its Impurities.

Similar Datasets

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