Research Of The Population Pharmacokinetic Model Of Levetiracetam And Multi-resistant Genes C3435T Polymorphism In Patients With Epilepsy

Objective:1. To get the population pharmacokinetic model of levetiracetam and provide thebasis for individualized medication;2. To learn about the relationship between C3435T in MDR1gene and response toantiepileptic drug treatment in epileptic adult patients in this area.Methods1. Determine blood concentration of levetiracetam by HPLC-UV;2. Genotypes of the MDR1C3435T polymorphism were determined by polymerasechain reaction (PCR) followed by restriction fragment length polymorphism(RFLP);3. Set up the population pharmacokinetic (PPK) model of levetiracetam combingwith physiological and biochemical indexes, blood concentration, MDR1C3435Tpolymorphism and drug combination, by NONMEM;4. Subjects were classified, some were resistant to antiepileptic drug treatment, theothers were responsive to the treatment. Comparing genotype and allele frequenciesbetween the RE and not RE groups by χ2test to learn about the relationship ofresistant to antiepileptic drug and MDR1C3435T polymorphism.Result1. The linearity was good within the range of1～80μg mL-1by the HPLC-UVdetection with the equation was y0.001x-0.00173(r2=0.9994). At threeconcentration, the extraction recoveries were86%～89%; the recoveries were99～101%; the intra and inter-day RSD was less than5%. The detection limit was0.5μg mL-1(S/N≥3).2. Of the99subjects, the patients number and genotype frequency of CC were33and33.3%, CT were52and52.6%、 TT were14and14.1%. Comparing the theoreticfrequency with actual frequency among the three group by SPSS soft, p value of theEP group was0.462. 3. Get PPK model of LEV with150blood samples and related index of99subjects.Final regression model with one compartment of LEV as follows:0.303CL2.450.227WT47e L h-1;V27.7L.The body weight (WT) was the most important factor affects thepharmacokinetic parameters and LEV’s clearance (CL).4. Of the RE group (47patients), the genotype frequency of CC was27.66%、 CTwas61.7%、TT was10.64%, allele frequency of C was58.51%、T was41.49%; Ofthe not RE group (52patients), the genotype frequency of CC was32.14%、 CT was50%、 TT was17.86%, allele frequency of C was57.14%, T was42.86%. Comparingeach group by genotype and allele frequencies, p value of the genotype was0.2, theallele was0.774.Conclusion1. With the accurate, rapid and stable characters, the HPLC-UV method is suitable forthe determination of concentrations of LEV in human plasma.2. The determination of genotypes of the C3435T polymorphism by polymerase chainreaction (PCR) followed by restriction fragment length polymorphism (RFLP) wasfeasible.3. The population pharmacokinetic final model of levetiracetam is stable, whoseaccuracy and precision were suitable, and wich can provide the basis forindividualized medication;4. There is no association between C3435T in MDR1gene and response toantiepileptic drug treatment in the epilepsy patients researched this area.