Abstract
Cefazolin sodium is an essential drug that is widely used in clinical therapy for certain infective diseases caused by bacteria. As drug impurities are considered to be one of the most important causes of drug safety issues, we studied embryotoxicity, cardiotoxicity, and neurotoxicity of nine cefazolin sodium impurities in zebrafish embryo and larvae for the objective control of impurity profiling. LC-MS/MS was employed to analyze the compound absorbance in vivo, and the structure-toxicity relationship was approached. Our results suggested that the structure of MMTD (2-mercapto-5-methyl-1, 3, 4-thiadiazole) is the main toxic functional group for embryo deformities; the 7-ACA (7-aminocephalosporanic acid) structure mainly affects motor nerve function; and both the MMTD and 7-ACA structures are responsible for cardiac effects. Impurity G (7-ACA) presented with the strongest toxicity; impurity A was most extensively absorbed to embryo and larvae; and impurity F (MMTD) exhibited the strongest apparent toxic effect; Therefore, impurities F and G should be monitored from the cefazolin sodium preparations.
Highlights
Cephalosporin has the characteristics of a wide-spectrum antibacterial drug, low toxicity, and resistance to penicillin enzymes
Using the animal model of zebrafish, we evaluated the toxicity of nine impurities of cefazolin sodium on embryonic development, neurobehavior, and cardiac function; and investigated the correlation between the structures of the impurities and toxicity reactions combined with the in vivo contents of the compounds
Among the impurities of cefazolin sodium, impurity G was the strongest one in toxicity, impurity A was the most absorbed by the body, and impurity F exhibited the strongest apparent toxic effect
Summary
Cephalosporin has the characteristics of a wide-spectrum antibacterial drug, low toxicity, and resistance to penicillin enzymes. Cephalosporin accounts for about 50% of the total sales of antibiotics in China; of this, 2% of the sales involve cefazolin sodium (unpublished data). A wide range of clinical applications has led to the continuous emergence of adverse drug reactions (ADRs) caused by cephalosporin. Fan et al analyzed 1,169 cases of cephalosporin-induced ADRs that were reported from 1998 to 2010 in 958 publications in China by using the bibliometrics method: the most frequent were systemic reactions (35.67%) followed by central and peripheral nervous system reactions (19.76%), and the occurrence of blood abnormality (13.94%). The familiar ADRs of cefazolin sodium include the common ADRs of cephalosporins (He, 2004; CFDA, 2014), but relatively high proportions of cardiovascular system reactions (16/152, 7.2%) and nervous system reactions (8/152, 5.3%) (He, 2004). The nervous system adverse reactions are considered to be from cephalosporin, which inhibits the combination of gamma aminobutyric acid to its receptors, blocks the synthesis and transport
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