Effect Of CYP2C19 Genetic Polymorphism On Pharmacokinetic Characterstics And 5-hydroxyl Metabolic Pathway Of Lansoprazole In Chinese Volunteers

Background:Lansoprazole is a safe and efficient proton pump inhibitor(H+-K+-ATP enzyme) of the first generation, which has been widely used in the treatment of peptic diseases. Some studys suggested that the clinical effect of the lansoprazole had significant individual differences. Now, there have been some related studies for this phenomenon, which mainly about the correlation of the CYP2C19 genetic polymorphism and the concentration of lansoprazole prototype. But some studys showed that lansoprazole is mainly metabolized by CYP2C19 and CYP3A4 in the liver, and the mainly metabolites were 5-hydroxy lansoprazole and lansoprazole sulphone, more metabolic pathways may produce much more influence. So this subject is going to more roundly explain the individual concentration differences of the lansoprazole by study the effect of CYP2C19 genetic polymorphism on pharmacokinetic characterstics and 5-hydroxyl metabolic pathway of lansoprazole.Objectives:This subject will study the effect of the CYP2C19 genetic polymorphism on the pharmacokinetic characterstics and 5-hydroxyl metabolic pathway of lansoprazole, which will more roundly explain the individual concentration differences of the lansoprazole. And it also provide a new perspective for drug metabolism study with polymorphisms and more metabolic pathways.Methods:1. Determination of lansoprazole and 5-hydroxy lansoprazole were explored and established in plasm with LC-MS and were put into practice based on demanding of analysis of biology sample.2.12 volunteers were choosed and collected 3 mL blood from extremitas superior. To distinguish mutant types and wild types,12 healthy volunteers were typed by using RFLP-PCR method.3. The mutant types and wild types all drip 30 mg lansoprazole and collected 3 mL blood to the heparinized tubes from extremitas superior at 0.0,0.17,0.33,0.67,0.83, 1,1.17,1.67,2.17,2.67,3.67,5.67,8.67,12.67h, centrifugalizing and obtaining blood plasma, according to the established method to determinate the concentration of lansoprazole and the data of 5-hydroxy lansoprazole4. According to the measured data of lansoprazole and 5-hydroxy lansoprazole, the main pharmacokinetic parameters of lansoprazole and AUCLPZ/AUC5-OH LPZ were calculated by DAS2.1 software. Analysed and compared the main pharmacokinetic parameters, AUCLPZ/AUC5-OH LPZ between wide types and mutant types.Results:1. The establishment of determination of lansoprazole and 5-hydroxy lansoprazole in plasma with LC-MS has good sensitivity and specificity and is consistent with demanding of analysis of biology sample.2.12 healthy subjects were typed by using RFLP-PCR method. The result showed that 8 subjects were mutant types(include mutant heterozygotes and mutant homozygote),4 subjects were wide types, accounted to 33.3% of total.3. The statistical results showed that after all the healthy volunteers were given 30 mg lansoprazole, the parameters of Cmax, AUCo-t, AUC0-∞,CLz of lansoprazole had significantly difference between the wide types and mutant types(P<0.05). The Cmax, AUCo-t, AUC0-∞. and (AUCLPZ/AUC5-OH LPZ) 0-πof the mutant types were equivalent to 1.551,2.381,2.572 and 0.428-fold as those of the wild types, respectively. However, the ratio of the AUCLPZ/AUC5-OH LPZ between the wide types and mutant types has extremely significant difference(P<0.01). The (AUCLPZ/AUC5-OH LPZ)o-t and (AUCLPZ/AUC5-OH LPZ)0-∞of the mutant types were equivalent to 3.602 and 4.083-fold as those of the wild types, respectively.Conclusions:The CYP2C19 genetic polymorphism, which has significant influence on the pharmacokinetic characterstics of the lansoprazole in Chinese volunteers (P<0.05), has very significant influence on the the 5-hydroxyl metabolic pathway of the lansoprazole (P<0.01). The result suggests that CYP2C19 genetic polymorphism is one of the important factors leading to individual concentration differences of the lansoprazole and has a better relevance with the 5-hydroxyl metabolic pathway.