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 (Δ-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.
Highlights
Ceftazidime (CAZ) is a third-generation cephalosporin that has been commonly used since the 1990s
OECD QSAR Toolbox 4.1 software was used to predict the structural alerts leading to genotoxicity
We predicted the genotoxicity of CAZ and its impurities via the following (Supplementary Table S1): (1) toxicity mechanisms including DNA binding and protein binding, (2) toxicity endpoint including carcinogenicity, in vitro mutagenicity test (Ames test), and in vivo mutagenicity
Summary
Ceftazidime (CAZ) is a third-generation cephalosporin that has been commonly used since the 1990s. It is widely used to treat infections, including sensitive strains and severe infections. In 2015, Ceftazidime-Averbatan was approved by the USFDA for the treatment of complicated urinary tract infections (cUTIs) and combined with metronidazole for the treatment of complicated intraabdominal infections (cIAIs). CAZ can be administered by intramuscular or intravenous injection with high blood concentration, low protein binding rate (10–17%), renal excretion (80–90%), wide. Toxicity Prediction of Ceftazidime Impurities distribution in vivo, and blood–brain barrier penetration (25%) (Zasowski et al, 2015; Falcone and Paterson, 2016). CAZ has induced common adverse reactions in the nervous system as well as blood, urinary, and digestive systems. There are few reports on the toxicity of CAZ impurities
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