| In the production and living activities of human beings,a variety of chemical substances will be produced,and some will directly or indirectly harm the health of human and other organisms.These substances are the object of environmental chemistry and also a kind of environmental pollutants.The pharmacokinetic study of these substances helps to understand the relationship between the dosage and the exposure level of the drug in the body.For example,K15 is the intermediate of medicine anti AIDS drug darunavir.In this study,the absorption kinetics of K15 in SD rat plasma was studied.By analyzing the data comprehensively and scientifically,we got the K15 absorption characteristics after oral and intravenous exposure,so as to complete the absorption kinetics research of K15 poisoned rats.ObjectiveTo observe the changes of plasma K15 concentration in SD rats after intragastric administration and intravenous injection of K15 at different doses,and to study the absorption characteristics of K15 chemicals through oral and intravenous exposure,so as to explore and complete the absorption kinetics of K15 poisoned rats.MethodsTo establish a LC-MS method for the determination of K15 in plasma of SD rats.The qualified SD rats were divided into low-dose gavage group(150 mg/kg),middle dose gavage group(450 mg/kg),high dose gavage group(1000 mg/kg),intravenous injection group(20 mg/kg),5 rats in each group,male,fasting before drinking.After the animals were infected,the blood was taken from the orbital venous plexus and the heparin anticoagulant.The amount of blood was 0.3 mL.The time of collecting blood samples in the gavage group was 5 min,10 min,20 min,30 min,45min,1 h,2 h,4 h,6 h,8 h,10 h,24 h and 48 h,respectively.The time of collecting blood samples from intravenous injection group was 5 min,10 min,20 min,30 min,40 min,50 min,60 min,75 min,90 min,105 min,2 h,3 h,6 h,8 h and 24 h,respectively.The plasma samples,adding internal standard solution(Lee of Shaaban 20 ng/mL 1 min)mixed vortex;vortex mixing centrifugal 20s,10 min(13200 RPM),taking the upper organic phase in a test tube,5mL analysis.Internal standard method was used for quantitative analysis,and the concentration of K15 in plasma was obtained.The main kinetic parameters of AUC,Cmax,Tmax and T1/2 were fitted by DAS pharmacokinetic software.Results1)The endogenous impurities in plasma did not interfere with the determination of K15.The extraction recoveries of K15 in plasma ranged from 52.9%-61.4%;interday precision ranged from 5.19%-8.14%;intraday precision ranged from 4.53%-6.60%;accuracy ranged from 96.1%-102.49%.The linear range of K15 was 25-1000ng/mL.The lower limit of quantitation of K15 was 25ng/mL(RSD=12.7%).The stability of K15 was in accordance with the requirements under various conditions.Therefore,this method was suitable for the analysis of K15 in plasma samples.2)The main pharmacokinetic parameters and absolute bioavailability of each group were as follows:After intragastric administration of K15 in doses of 100 mg/kg,450 mg/kg,1000 mg/kg,intravenous injection in dose of 20 mg/kg,the AUC(o-t)of K15 were 9661.9±974.6,16197.7±2607.1,46157.4±8416.2,1620.0±439.6 ?g/L*h;T1/2 were 0.948 ± 0.12,5.53±7.37,4.44±2.61,0.875±0.286h;Tmax were 0.567±0.25,0.533±0.21,0.75±0.18,0.083 h;Cmax were 7503.4±1937.5,8023.0±2441.7,19074.0±10423.6,2329.6±586.8 ?g/L;bioavailabiity were 79.5%,44.4%,57.0%?ConclusionThe results of the study showed that K15 had a certain amount of systemic exposure in rats after gavage to rats,and the bioavailability decreased with the increase of the dose.The exposure level of K15 in rats is positively correlated with the dose of exposure,and the exposure of the system increases with the increase of dose.K15 at 100 and 450 mg/kg,the no significant increase in the body of the Cmax,but at a dose of 1000 mg/kg,Cma,increased significantly.With the increase of dose,the T1/2 value of K15 increased significantly in rats,suggesting that the exposure time increased significantly with the increase of dose. |
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