Study Of Cannabinol Carbamates On The Pharmacokinetics And Tissue Distribution In Rats

Cannabinol（CBD）,as the newly approved drug for the treatment of epilepsy,has been proved to have therapeutic potential in many pharmacological fields.We introduced carbamate based on its structure and verified its therapeutic effect on Alzheimer’s disease.The study compares the blood concentration of different amino structures in the body and the difference of brain concentration,and expects to obtain high value derivatives of CBD structure.In this study,a UPLC-MS method was established to detect the plasma concentration of CBD carbamates in rats,and further study the pharmacokinetics（PK）characteristics of CBD carbamates in rats after administration.The study of tissue distribution can promote the discovery of derivatives modified by CBD structure and provide important reference for drug synthesis by collecting tissues at five time points,detecting their concentrations and comparing the concentration differences of brain and other organs.1.UPLC-MS Determination of CBD carbamates concentration in rat plasmaA rapid and highly specific UPLC-MS method was established to detect CBD（L0）and four CBD derivatives（L1-L4）in plasma at the same time,and the methodological validation was carried out.The results showed that the established standard curve,extraction recovery and matrix effect,precision and accuracy,stability,etc.all met the quantitative requirements of biological samples,and could be used for the detection of CBD derivatives.2.The pharmacokinetic study of CBD carbamatesThe dosage of 15 mg/kg was designed as the drug administration scheme.The study found that after gavage of the same dose of CBD and CBD carbamates,the blood concentration of CBD carbamates increased,especially the increase of L2 and L4 containing tertiary amine was the most significant.The peak concentration was higher,and the area under the blood concentration-time curve was higher.AUC_0-Twere 561.35±104.32μg/L*h and 521.56±133.68μg/L*h,respectively,while L0was only 157.50±10.61μg/L*h.L1 has a faster peak time and a faster metabolism,and its decomposition produces CBD.L2 has a slow metabolism,and the rest is not much different from CBD.The peak concentration of plasma in L2 and L4 was higher,and the AUC was much higher than the others.These results indicated that the two drugs were well absorbed and had high bioavailability,but the elimination half-life t_1/2was short.The synthesis of new CBD carbamates could be improved on this basis.Through these pharmacokinetic parameters,it was clear that the modification of L2containing methylethylamine and L4 containing tert-benzylamine was relatively successful,C_maxand AUC_0-Tincreased significantly.3.Tissue distribution of CBD carbamates in ratsTo investigate the distribution of L2 and L4 in brain,heart,liver,spleen,lung and kidney of rats at 0.5,1,2,4,8 h after administration of L2 and L4 by intragastric administration.After 1 hour of gastric administration,L2 was rapidly distributed in various tissues.At 1 hour,it reached its highest concentration in the heart,liver,spleen,lung,and kidney organs,and at 2 hours in the brain,it reached a maximum concentration of 56.04±6.76 ng/g.The tissue concentration from high to low was in the order of kidney>liver>spleen>lung>heart>brain.After 8 hours,the drug concentration in each tissue decreased rapidly,indicating that it was not easy to accumulate in the body.After 2 hours of gavage administration,L4 rapidly distributed in various tissues,with a rapid increase in drug concentration between 0.5-2 hours.It reached its highest concentration in the heart,liver,spleen,lungs,and kidney organs at 2 hours,and reached its peak at 18.6±2.48 ng/g at 1 hour in the brain.The order of concentration from high to low is lung>heart>spleen>kidney>liver>brain.At 8hours,the tissue content is still relatively high,indicating that it metabolizes slowly in the tissue and is easy to accumulate in the body.Compared with L4,L2 has a concentration twice higher in the brain and is less likely to accumulate in the body,indicating that L2 has certain advantages over L4.