Study On The In Vivo Process Of Bloven Enantiomers

Objective: To investigate the pharmacokinetics of ibuprofen isomer in rats;the pharmacodynamics and pharmacokinetics and their correlation based on New Zealand rabbit fever model.The toxicity of racemate ibuprofen,and S-ibuprofen was also compared to provide evidence for ibuprofen isomer product development and clinical rational use.Methods:(1)A HPLC analytical method was developed and validated to detect the plasma concentration of chiral ibuprofen;(2)The pharmacokinetics of racemic ibuprofen with three doses(high,medium and low dose)after a single dose treated by intragastric administration in rats were studied.(3)A single dose intravenous injection with racemate ibuprofen ? R-ibuprofen and S-ibuprofen were given to fever rabbit respectively to study their pharmacodynamics and pharmacokinetics and their relationships.(4)Following 5 days continuous intragastric administration to a rat model with ibuprofen,S-ibuprofen respectively,the toxicity of ibuprofen isomers were compared using hematoxylin-eosin(HE)staining and plasma biochemicalResults:(1)A simple and stable method of HPLC was established to determine the plasma concentration of ibuprofen enantiomers.The standard curve equations of R-ibuprofen as well as S-ibuprofen havebeen achieved with Y=0.2664X-0.0221(r2=0.9996)and Y=0.2569X-0.0193(r2=0.9992),respectively.There was a good linear relationship between the peak area ratio and concentration(0.3125~50?g·mL-1)of R-ibuprofen and S-ibuprofen,with the lower limit quantification of 0.3125?g·mL-1.The methods were validated and reached the analytical demand.(2)The pharmacokinetic parameters for three different groups(low,middle and high dose)were obtained.The parameters of R-ibuprofen were as follows: Cmax 15.23±2.15,18.23±2.54,and 57.58±5.94?g/mL;AUC0-t 15.23±2.15,18.23±2.54,and 57.58±5.94?g·ml-1·h-1;CLz 0.86±0.11,1.39±0.12,and 0.88±0.10 L·kg-1· h-1.The parameters of S-ibuprofen were as follows: Cmax29.69±2.55,39.63±2.50,and 83.32±9.27 ?g/mL;AUC0-t96.17±13.42,117.90±18.19,and 259.35±52.24 ?g·ml-1·h-1;CLz0.11±0.03 ? 0.19±0.05 ? 0.16±0.03 L ·kg-1· h-1.(3)Pharmacokinetic parameters of ibuprofen after intravenous administration in New Zealand rabbits were as follows : Cmax85.00±6.61?g/mL,AUC0-t47.95±5.55?g·mL-1·h-1,CLz0.62±0.08 for laevo isomer,Cmax74.71±9.65?g/mL,AUC0-t47.49±9.88?g·mL-1·h-1,and CLz0.65±0.14 for Right-handed isomer.The pharmacokinetic parameters of intravenous S-ibuprofen in New Zealand rabbits were as follows :Cmax:49.44±6.67?g/mL,AUC0-t:29.12±4.53?g·mL-1·h-1,CLz:0.52±0.07.The pharmacokinetic parameters of R-ibuprofen after intravenousadministration in New Zealand rabbits were as follows: Cmax42.40±8.41?g/mL,AUC0-t 22.15±4.76?g·mL-1·h-1,CLz 0.70±0.16 for laevo isomer,Cmax 12.96±2.70?g/mL,AUC0-t 9.34±2.26?g·mL-1·h-1,CLz 1.64±0.32 for Right-handed isomer.After treated with intravenously injected endotoxin for half an hour,the body temperature of New Zealand rabbits in ibuprofen group decreased significantly.After forty minutes,the body temperature of rabbits in S-ibuprofen group dropped,while there was no significant decrease of that in R-ibuprofen group.Correlating pharmacodynamics parameters with pharmacokinetics parameters indicated that pharmacological effect of ibuprofen lags behind its plasma concentration.(4)The body weight index treated with S-ibuprofen group were heavier than those rats treated in ibuprofen(P<0.05).With regard to biochemical indexes,the aspartate aminotransferase index of Ibuprofen group was higher than that of S-ibuprofen group(P<0.05).The Urea nitrogen index of Ibuprofen group was higher than that of S-ibuprofen group(P<0.05).The Creatinine index Ibuprofen group was higher than that of S-ibuprofen group(P<0.05).Based on general observation of gastrointestinal tissue and pathological index,the injury of the intestinal mucosa caused by ibuprofen was more serious than that of S-ibuprofen(P<0.05).Simultaneously,intestinal mucosal injury caused by ibuprofen was more serious than that of S-ibuprofen group(P<0.05)by he histologicalevaluation.Conclusion:(1)The established method of HPLC for in vivo detection is stable and feasible.(2)S-ibuprofen and R-ibuprofen have a certain linear dynamic characteristic on the rat model.The process for absorption of S-ibuprofen in vivo is longer than that of ibuprofen with slower elimination;(3)The cooling effect of S-ibuprofen was similar to that of ibuprofen,however,the dose of S-ibuprofen is only half of that for ibuprofen;(4)the S-ibuprofen shows better performance than that of ibuprofen.Hence,patients with diseases including rheumatoid arthritis should select S-ibuprofen as a prioritized drug instead of ibuprofen to reduce the risk of adverse reaction when they have a necessity for the high-dose or long-term intake of such medicines.