Effects Of Non-enzymatic Glycation On Binding Of Human Serum Albumin To Etoposide And Paclitaxel

The significant increased glucose concentration in the blood of diabetic patients leads to proteins undergo a chemical reaction called non-enzymatic glycation reaction.This reaction is the initial factor that causes diabetic complications.Human serum albumin(HSA)is the most abundant protein in human plasma,which can bind and transport various drugs.HSA has a higher chance of non-enzymatic glycation than other proteins,and a higher level of nonenzymatic glycation can change the binding behavior of HSA to drugs,which may affect the pharmacokinetics and pharmacodynamics of drugs.Cancer is the leading cause of death and an important barrier to improving life expectancy in countries around the world.The study found that adults with impaired glucose tolerance had a higher risk of cancer,and that diabetics were more likely to take cancer drugs than nondiabetics.Chemotherapeutic drugs are usually combined with HSA to form a complex for transport,after which the free drugs can be dissociated to exert pharmacological activity.Etoposide and paclitaxel are two commonly used chemotherapeutic drugs in clinic,but they often cause toxic and side effects in the treatment process.Due to their high binding ratio with HSA,how non-enzymatic glycation of HSA affects its binding and transport with the two chemotherapy drugs and the possible adverse reactions need to be further studied.In this paper,we combined the simulation docking technology with nano-liquid chromatography-tandem mass spectrometry with multiple-reaction monitoring(nLC-MS/MSMRM)technology and compared the non-enzymatic glycation levels of drug-HSA binding sites in diabetic and healthy subjects,to analyze whether non-enzymatic glycation affects the binding of HSA to two chemotherapy drugs and screen out potential sites that affect the drug binding.In order to further explore the effect of this reaction on binding and verify the above results,the effects of HSA non-enzymatic glycation on free chemotherapeutic drugs concentration in plasma and pharmacokinetics of drugs were studied by in vitro and in vivo experiments combining ultrafiltration and LC-MS/MS-MRM quantitative technique.It was found that HSA non-enzymatic glycation sites weakened the binding ability of etoposide to plasma protein,but had no significant effect on the binding ability of paclitaxel.When the binding ability of plasma protein to drug is weakened,the concentration of free drugs in plasma is increased and the side effects are enhanced.Therefore,when using etoposide,it is necessary to carry out more strict blood concentration monitoring for patients with cancer complicated with diabetes,and adjust the administration regimen accordingly to reduce or avoid the occurrence of toxic reactions.The results of this study provide a risk assessment for the use of specific chemotherapeutic agents in patients with cancer complicated with diabetes,and provide reference value for the selection of clinical drugs.