ABSTRACT
@#Cadmium is a toxic heavy metal commonly seen in the environment. Long-term exposure to low dose of cadmium has toxic effects on multiple systems and organs of human body. The kinetic model is a new technology to quantitatively evaluate the correlation between internal and external exposure of chemicals, which can provide reliable information for risk assessment. There are two kinetic models of cadmium: toxicokinetic model (TK) and physiologically-based toxicokinetic model (PBTK). They have played a role in the establishment of cadmium exposure limits and risk prediction. This article reviews the construction, development, and limitations of the two models, and looks forward to the direction in which the models can be further optimized, providing the reference for risk assessment of cadmium exposure in China.
ABSTRACT
Liquid chromatography tandem mass spectrometry (LC-MS/MS) has gradually become a promising alternative to ligand binding assay for the bioanalysis of biotherapeutic molecules,due to its rapid method development and high accuracy.In this study,we established a new LC-MS/MS method for the determination of the anti-sclerostin monoclonal antibody (SHR-1222) in cynomolgus monkey serum,and compared it to a previous electrochemiluminescence method.The antibody was quantified by detecting the surrogate peptide obtained by trypsin digestion.The surrogate peptide was carefully selected by investigating its uniqueness,stability and MS response.The quantitative range of the pro-posed method was 2.00-500 μg/mL,and this verified method was successfully applied to the tox-icokinetic assessment of SHR-1222 in cynomolgus monkey serum.It was found that the concentrations of SHR-1222 in cynomolgus monkeys displayed an excellent agreement between the LC-MS/MS and electrochemiluminescence methods (ratios of drug exposure,0.8-1.0).Notably,two monkeys in the 60 mg/kg dose group had abnormal profiles with a low detection value of SHR-1222 in their individual sample.Combining the high-level anti-drug antibodies (ADAs) in these samples and the consistent quantitative results of the two methods,we found that the decreased concentration of SHR-1222 was due to the accelerated clearance mediated by ADAs rather than the interference of ADAs to the detection platform.Taken together,we successfully developed an accurate,efficient and cost-effective LC-MS/MS method for the quantification of SHR-1222 in serum samples,which could serve as a powerful tool to improve the preclinical development of antibody drugs.
ABSTRACT
Recent researches on clinically used triazole antifungal reagents are focused on their pharmacokinetic disadvantage which increases the probability of inducing adverse effects in patients. For this point, in the present laboratory, Chemon Inc., has investigated new antifungal reactive compounds, KAF-200522 and its chloride form, KAF-200522 . HCl, which has a modified triazole structure. Pharmacokinetic data were measured with LC-MS/MS in male mice which were orally treated with the above compounds at 10 mg/kg. Tmax and t1/2 of KAF-200522 . HCl were comparable to KAF-200522, but AUC and Cmax were 1.4 and 1.6 times higher than those of KAF-200522, respectively. In beagle dogs, AUC and Cmax of KAF-200522 . HCl were 2.7 and 1.4 times higher than those of KAF-200522, and t1/2 was 3.5 times higher than that of KAF-200522. Moreover, in beagle dogs, the oral bioavailability value of KAF-200522 . HCl was revealed as 31.0% to contrast to 6.2% of KAF-200522. In 1-week repeated oral treatment toxicity study of KAF-200522 in male rats, inhibition of body weight gain was observed in 120 mg/kg treatment group, and loss of body weight was observed in 600 mg/kg treatment group. In the toxicokinetic study of KAF-200522, no accumulation after the systemic exposure was observed. In conclusion, as to the new antifungal drug development, KAF-200522 . HCl was considered to be advantageous in pharmacokinetic characteristics compared to KAF-200522.
Subject(s)
Animals , Dogs , Humans , Male , Mice , Rats , Area Under Curve , Biological Availability , Body Weight , Indicators and Reagents , Models, AnimalABSTRACT
El cianuro es uno de los tóxicos más peligrosos por su rápida y potente acción, muchas veces letal. Los diferentes tratamientos de la intoxicación tienen su base o explicación en el conocimiento de la toxicocinética y la toxicodinamia. La revisión de la toxicocinética del cianuro muestra que, si bien la vía de la tiosulfato-cianuro sulfotransferasa (rodanasa) es la principal vía metabólica, el complejo con albúmina sérica sería el primer proceso de detoxificación del cianuro en el metabolismo normal. El efecto protector de formadores de cianhidrinas en casos de intoxicación sigue siendo evaluado a nivel experimental. Los estudios actuales sobre la toxicodinamia del cianuro se enfocan en la afinidad de la unión del cianuro al centro binuclear hemo a3-CuB de la citocromo oxidasa en sus diferentes estados redox y enel mecanismo de inhibición de enzimas antioxidantes. Un mayor y mejor entendimiento de la detoxificación del cianuro así como de los mecanismos de acción tóxica podrían llevar al desarrollo de potenciales antídotos.
Cyanide is one of the most dangerous poisons because of its rapid and potent toxicity, most times with lethal outcomes. Different poisoning treatments are based on knowledge of cyanides toxicokinetic and toxicodynamic. The review of cyanides toxicokinetics shows that, although thiosulfate-cyanide sulfotransferase (rhodanese) is the major metabolic pathway, binding serum albumin would be the first process of detoxification of cyanide in normal metabolism. The protective effect of cyanohydrin formers in cases of poisoning remains experimentally evaluated. Cyanides binding affinity to the binuclear center heme a3-CuB of cytochrome oxidase within their different redox states and cyanides mechanism of inhibition of antioxidant enzymes are currently still being investigated. More and better understanding of cyanides detoxification pathways and/or mechanisms of toxic action could lead to the development of new potential antidotes.