Pharmacokinetic Studies Of Poloxamer 188 In Rats

Poloxamer 188,as one of the most commonly used pharmaceutical excipients,has a unique physicochemical property and good biocompatibility,is playing an increasingly extensive role in the field of medicine.Currently,there are few studies on the pharmacokinetics of poloxamer 188 in vivo,and the reported analytical methods cannot accurately evaluate the pharmacokinetic behavior in vivo.It is necessary to develop a method for quantitative analysis of poloxamer 188 in vivo with high sensitivity and specificity.In this study,the LC-MS/MS^ALL method for absolute quantitative analysis of poloxamer 188 in biological substrates was established for the first time,and it is based on MS^ALL technique of quadrupole time of flight mass spectrometer?Triple TOF5600+?.In the scanning mode of MS^ALL,the countless poloxamer 188 precursor ions are all through in Q1,and all of them are transferred to Q2 fragmentation,all of which are detected by TOF.The results show that,under the condition of high collision energy?CE?,uncountable poloxamer 188 precursor ion can be cracked to produce a limited number of characteristic fragment ions,among which 2 Polypropylene oxide?PPO?subunit,m/z 117.0899,has high sensitivity and good specificity,and can be used as the characteristic ion to realize the absolute quantitative analysis of poloxamer 188.In this study,the method of gradient elution was used to separate poloxamer 188by chromatographic method.Chromatographic method:The solvent A is 0.1%formic acid–water.The solvent B is 0.1%formic-acetonitrile:isopropanol?2:3,v/v?.The chromatographic Column is PLRP-S Reversed-Phase Column?50×4.6 mm,8?m,1000??,the flow rate of 0.8 mL/min.The quantitative linear range was 0.1¹0.0?g/mL,and the pretreatment method is protein precipitatation method.To ensure the reliability of the quantitative results of the method,the methodological verification was carried out according to the relevant FDA guiding principles.The results show that the method is accurate and reliable and meets the basic requirements of the relevant FDA guiding principles.In this study,the pharmacokinetics of poloxamer 188 in SD rats were studied using established quantitative analysis methods.The dose of caudal vein was 5 mg/kg.The plasma concentration was measured and the drug concentration-time curve was drawn.The drug generation parameters calculated are as follows:t_1/2 was 2.042±1.131 h,C_maxax was 11.332±3.12?g/L,Vd was 5.111±3.215 L/kg,AUC_?0-t?was 3.048±0.604?g/L*h,CL was 1.693±0.327 L/h/kg.This indicated that when poloxamer 188 was administered through the caudal vein,it could be rapidly distributed to all tissues with a high clearance rate.To further explore the distribution of poloxamer 188 in organs and tissues,the drug was administered by the rat tail vein at a dose of 5 mg/kg.At 0.25h,1h and 4h after administration,8 kinds of tissues in the rat body were adopted,namely heart,liver,spleen,lung,kidney,stomach,muscle and brain.And the concentration of poloxamer188 was determined The results showed that the distribution concentration of poloxamer 188 was the highest in the kidney,which may cause some accumulation and produce nephrotoxicity.The concentration of poloxamer 188 in the liver and stomach was lower than the kidney.The reason may be that the liver is rich in enzymes that can produce a variety of biochemical reactions.The stomach has more blood vessels and higher blood flow per unit weight.The concentration of poloxamer 188 in heart,lung,muscle and spleen was not high.This suggests that poloxamer 188 has a low risk of accumulation in these organizations.No analytical material was detected in brain tissue,indicating that poloxamer 188 could not enter brain tissue through the blood-brain barrier.