The Pharmacokinetics Investigations Of Oxacarbazipine And Carbamazipine And The Primary Theoretic Analysis Of The Metabolism Difference Between Them

OBJECT Oxcarbazepine (OCBZ) is a new anti-epileptic drug which has gradually become the substitute of carbamazepine(CBZ) used as the first line antiepileptic at present ,for its good tolerance,poor side effects and less drugs interreaction. OCBZ is the 10-keto analogue of .Their chemical structures are very similar ,but the pharmacokinetic profile and the clinical pharmacologic actions have great difference. We studied pharmacokinetic characteristics of OCBZ and CBZ ,assessed the bioequivalence of test tablet and reference tablet of OCBZ after a single dose of the CBZ and OCBZ in healthy volunteers.Due to interindividual variability in pharmacokinetic behavior of CBZ ,a primary individualized dosing regimen ,which can make clinical medication more accurate and rational, was tried to carry out in this approach. We also studied the possible mechanisms of metabolism difference between OCBZ and CBZ in the microview. METHOD1.The study of pharmacokinetic profile of OCBZ: A single 300mg dose of test tablet(TT) and reference tablet(RT) of OCBZ study was carried out in 20 healthy volunteers with a two-period ,crossover randomized design.2.The study of pharmacokinetic profile of CBZ : The plasma samples were determined by HPLC after single oral administration of CBZ 200mg in 12 healthy volunteers.3.The design of CBZ individualized dosing regimens: The gradual regressive analysis was carried out between population parameters and individual internal agents ,which were obtained by phamiacokinetics parameters in 12 healthy volunteers of CBZ study,using PLS method in Moe software QuaSar mode to establish a relationship ofthem. Using predictive error (PE=YobS-Yprep) and coefficient correlation (R=Yprep : Yobs) as the estimatd index, and we tried to predict the individualized dosing regimens using parameter method and plasma drug concentration one point method.4.The primary theoretic analysis the metaboliam difference: To calculate the surface charge value of three molecules of CBZ , OCBZ and MHD ,after constructing and optimizing three dimensional structure of them through MMF94 procedure MOE software;To dock with crystal structure of CYP3A4 and CYP2C8 through the D0CK5 software;To score the bonding energy through amber99 force field. ■ RESULT1 The study of pharmacokinetic profile of OCBZ: The main pharmacokinetics parameters of TT and RT were as follow: Cmax were 0.94±0.44 and 0.93±0.41 jj.g/ml, Tpeak were 1.07±0.35 and 0.99±0.36h , AUC were 2.40±0.52 and 2.20±0.43(ug.h)/ml, lm were 2.41±0.60 and 2.40±0.58h Respectively .The relative bioavailability of TT was 94.7±18.2% compared to RT .The result indicated there was no significant difference between the two formulations and they were bioequiovalent.2.The study of pharmacokinetic profile of CBZ : The calibration curve of CBZ was linear within the range of 0.05~10^g/ml, the limit concentration of detection in CBZ was 0.05jig/ml, the average recovery was 94.4% .The determined value of main pharmacokinetics parameters were 4.71±0.99(ig/ml for Cmax, 16±12h for Tpeak, 361.62±49.43ug.h/ml for AUC , 38.39±6.37 h for tm, respectively .The blood sample concentration calculated by 3P97 procedure was fitted to single compartment model of first-order absorption.3.The design of CBZ individualized dosing regimens: After cross-validation, a mostoptimized and fitted gradual regressive equation which can take information of predictive value of individual parameters was as follow: Ka=0.6789-0.0035X2-0.0722X3-0.0017X4-0.0026X6 Ke=0.02714-0.0005 Xi+O.00009X3.0.00175 X5+0.00029 X*, Vd=1.2734+0.00841Xi-0.01084X2-0.06398X3CL=0.03423-0.01404X2.0.00759X3-0.00211X5. The matched-pairs t- test analysis showed there was no significant difference between the parameters of predictive value and true valueC P>0.05 ),the coefficient correlation of C72 of predictive value and true value is more than 0.9.4.The primary theoretic analysis the metaboliam difference: There exist better bonding mode and less orientation selectivity between three ligands and CYP3A4. Unless the bonding mode between porphyrin ring and aromatic ring like OCBZ and MHD, there exist one certain bonding mode between the site of 10,11 of CBZ and CYP3A4 which can lead to be oxidated the CBZ-E. The Docking result to CYP2C8 proved that There exist less bonding mode and much more orientation selectivity between OCBZ^ CBZ and CYP2C8, the main products are possibily the benzene ring oxide. CONCLUSION This research proved that due to the bioequvolence of two formulations , the domestic tablet of OCBZ can become the substitute of import tablet ,which may greatly cut down the patient therapy expense and make it more popular in the clinical epileptic therapy .The individual dosing regimens established in this approach have been proved to be more accurate and reliable compared to the tranditional method for the patient received CBZ long-term .Unlike OCBZ and MHD ,the charge on the sites connected to the 10 and 11 of CBZ was very similar to those of benzene-ring ,which indicated the carbon of two sites possess aromaticity and participate the mixed change to cause ring-oxidizing metabolism product whichmay bring about clinical adverse effects . So the possibility of bonding mode and hydric-aromaticity are two keys to the metabolism difference between CBZ andOCBZ.