Studies On Pharmacokinetics Of Chiral Drug Ibuprofe

Ibuprofen is a 2-aryl-propionic acid non-steroidal anti-inflammatory drug(NSAIDs).Since it was developed in UK in 1969,Ibuprofen has been widely used clinically because of its strong anti-inflammatory,antipyretic, and analgesic effects and limited adverse effects.Ibuprofen has two optical enantiomers,R-type and S-type,since its side chain has a chiral carbon atom. Studies have demonstrated that the right S-ibuprofen of the enantiomers inhibited pharmacological activity of generating prostaglandin.Previous animal experiment studies have shown that after administration of racemic ibuprofen to animals,R-ibuprofen could unilaterally converse into S-ibuprofen through generating coenzyme a Sulfatide in the body.Currently there are various commercial Ibuprofen preparations,the effective time and pharmacodynamic intensity of which vary.In recent years,with the development of analytical methods and facilities,the micro-determination of optical isomers of the ibuprofen in biological samples becomes possible. Understanding the pharmacokinetics characteristics of the optical isomers of the ibuprofen in the human body,particularly the impact of its release rate, will be significant in directing its clinical applications.In this study used racemic(rac-) ordinary ibuprofen tablets(IR) and sustained-release capsule(SR) to explore the pharmacokinetic process of the different release rate of optical enantiomers in healthy volunteers.Each volunteer was given a 600mg dose of different ibuprofen preparations respectively by the dual-channel crossover method.Rac-ibuprofen, S-ibuprofen and R-ibuprofen serum concentrations of different times were measured 24 hours after administration of ibuprofen.The pharmacokinetic parameters of different ibuprofen preparation in serum were analyzed by using non-linear and least-squares method.We evaluated objectively the differences of pharmacokinetics characteristics of enantiomers of ibuprofen in vivo by statistical analysis.The pharmacokinetic parameters of rac-ibuprofen in the human body were shown as follows.Rac-ibuprofen Cmax were 46.21±8.20μg·mL^-1 and 25.11±5.71μg·mL^-1,IR was significantly higher than SR(P<0.0001);tmax were 2.83±1.03h and 4.08±0.67h,IR also significantly shorter than SR(P <0.01);AUC were 192.90±43.47μg·mL^-1 and 195.90±31.69μg·mL^-1,no significant difference between IR and SR.MRT were 4.34±0.89h and 7.01±1.29h,SR significantly longer than the IR(P<0.0001).k_el were 0.54±0.16h^-1 and 0.24±0.09h^-1,IR significantly faster than the SR(P<0.01). The results show that the release rate affets the pharmacokinetics characteristics of rac-ibuprofen after administration of IR and SR to the healthy volunteers.Compared with IR,SR had a longer time to peak,a lower peak concentration,a longer residence time and a slower elimination rate in the human body.The pharmacokinetics characteristics of rac-ibuprofen made it remain at a relatively high concentration level in blood,which helped to prolong the pharmacological effect and made it better suited for the normal purpose and requirement of the drug in clinic.The results showed that Cmax of R- and S-ibuprofen were 12.24±3.79μg·mL^-1 and 12.38±3.55μg·mL^-1 after oral administration of SR,R- and S-ibuprofen the Cmax were 20.82±5.90μg·mL^-1 and 23.46±7.30μg·mL^-1 after oral administration of IR.Peak concentrations of two ibuprofen enantiomers of IR were significantly higher than SR(P<0.001).Whatever the release rate is peak concentrations of R-ibuprofen were significantly higher than S-ibuprofen,which demonstrated that the R-ibuprofen conversed into the S-ibuprofen in the human body.The tmax of R- and S-ibuprofen were 3.58±0.51h and 5.08±1.38h after oral administration of SR,respectively.Tmax of R- and S-ibuprofen were 2.96±1.18 h and 3.00±1.35 h after oral administration of IR,respectively. Peak time of R- and S- ibuprofen of IR were significantly shorter than that of SR(P<0.01),which was consistent with the results of rac-.The AUC of R- and S-ibuprofen were 55.38±17.79μg·h·mL^-1 and 92.51±30.68μg·h·mL^-1 after administration of SR ibuprofen,respectively. The AUC of R- and S-ibuprofen were 65.94±20.06μg·h·mL^-1 and 100.81±32.28μg·h·mL^-1 after administration of IR,respectively.The results showed that AUC of IR larger than that of SR and AUC of S-ibuprofen larger than that of R-ibuprofen(P<0.01),which appeared to tendency of chiral conversion from R-ibuprofen to S- ibuprofen in one-way.The MRT of R- and S-ibuprofen were 5.52±1.25h and 7.04±1.30h after oral administration of SR,respectively.The MRT of R- and S-ibuprofen were 3.43±0.64h and 4.51±0.79h after oral administration of IR,respectively.The MRT of R- and S-ibuprofen of SR increased significantly(P<0.0001).The results demonstrated that the increase of the residence time of ibuprofen in the absorption site will help to improve the chiral conversion rate of Ibuprofen from the poor enantiomer to excellent.The kel of R- and S-ibuprofen were 0.28±0.11h^-1 and 0.27±0.13h^-1 after oral administration of SR,respectively.The kel of R- and S-ibuprofen were 0.58±0.14h^-1 and 0.41±0.12h^-1 after oral administration of IR, respectively.The results showed that elimination of R- and S- ibuprofen of IR were significantly faster than that of SR in the human body(P<0.01).In addition,we compared the AUC ratio of R- and S-ibuprofen(S/R_AUC) after administration of IR and SR.The results showed that S/R_AUC of SR was greater than that of IR,and S/R_AUC in serum concentrations was significantly higher than that of IR after 6 h administration of ibuprofen(P<0.01),which indicated that ibuprofen also experienced the process of chiral conversion in the human body like as in the experimental animals.This study defined that the pharmacokinetic characteristics of the racemic ibuprofen and the optical isomers in healthy volunteers,and effects of the release rate on the pharmacokinetics characteristics and chiral conversion process.The results showed that the clinical effects of racemic ibuprofen varied depending on its absorption rate,and the clinical pharmacology activity of sustained-release preparation was stronger than that of immediate-release preparation.The results of this study provided valuable scientific basis for accurate and reasonable use of the drug,to maximize the clinical efficacy and reduce the incidence of adverse reactions,as well as to further improve the administration of dosage forms.In addition,the results will fill a blank in studying the pharmacokinetics of chiral drugs,which also provides an important reference value in studying the pharmacokinetics of other chiral drugs and perfecting theoretical systems domestically and abroad.