Effect Of CYP3A5, CYP2C19 Gene Polymorphism On Pharmacokinetic Characteristics Of Voriconazole In Chinese Volunteers

Background:Voriconazole is a new second-generation triazole antifungal agent, which undergoes a metabolism involving cytochrome P450(CYP) enzyme isoforms CYP2C19 and CYP3A4. However, Chinese people possess a very low frequency of polymorphism in CYP3A4. CYP3A4 and CYP3A5 often affects same substrate drug's pharmacokinetics together. Studies have shown that CYP3A5 and CYP2C19 do exist gene polymorphism and play important roles in many drugs' pharmacokinetics. Therefore, it is important to study the effect of CYP3A5 and CYP2C19 gene polymorphism on the pharmacokinetic of voriconazole to the clinical application of it.Objectives:To study the effect of CYP3A5, CYP2C19 gene polymorphism in Chinese people on the pharmacokinetic characteristics of voriconazole and instruct the reasonable clinical application of voriconazole by the feature of gene polymorphism.Methods:1 An LC-MS method for the determination of voriconazole in plasma was established and successfully applied to the pharmacokinetic study of voriconazole in Chinese people.2 20 volunteers were choosed according to pharmacokinetic standard. Then genotyping of CYP3A5 and CYP2C19 was made with the method of polymerase chain reaction-restriction fragment length polymorphism targeted at healthy volunteers'blood (wild type, heterozygous and homozygous).3 After a single oral dose 200 mg voriconazole tablets,5mL blood plasma were collected to the heparinized tubes at the lines of 0.0,0.25,0.5,0.75,1.0,1.5 2.0,3.0,4.0,6.0,8.0,12.0,24.0,36.0h. The blood plasma was obtained by entrifugalization and the concentration of voriconazole plasma was determinatied using the above LC-MS method.4 According to the measured data of voriconazole concentration of plasma, the main pharmacokinetic parameters of voriconazole were calculated by DAS 2.1 software, analysed and compared the voriconazole human pharmacokinetic characteristics of the wild type, heterozygous and homozygous by SPSS 17.0.Results:1 The establishment of determination of voriconazole in plasm with LC-MS has good sensitivity and specificity and is consistent with demanding of analysis of biology sample.2 Genotyping of 20 healthy volunteers showed that there are 3 people carrying CYP3A5*1/*1,5 people carrying CYP3A5*1/*3 and 12 people carrying CYP3A5*3/*3; there are 7 people carrying CYP2C19*1/*1,7 people carrying heterozygous (CYP2C19*1/*3,CYP2C19*1/*2) and 5 people carrying homozygous (CYP2C19*2/*2,CYP2C19*2/*3,CYP2C19*3/*3)3 Voriconazole pharmacokinetic characteristics in Chinses people by binding CYP3A5 and CYP2C19 was studied. It is found that CYP3A5 gene polymorphism do not affect any pharmacokinetic parameters of voriconazole (P>0.05), cueing that CYP3A5 gene polymorphism do not affect the pharmacokinetic parameters of voriconazole. It is found that the main pharmacokinetic parameters of AUC0-36,AUC0-x of CYP2C19 homozygous was notable higher than wild type and the heterozygous (P<0.05), the parameter of CL/F was notable lower than the wild type (P<0.05) at dose of 200mg, but the parameters of T1/2, Cmax had no statistical differences (P>0.05) cueing that CYP2C19 gene polymorphism do affect the pharmacokinetic parameters of voriconazole.Conclusions:CYP2C19 gene polymorphism do affect the pharmacokinetic parameters of voriconazole and CYP3A5 gene polymorphism do not affect the pharmacokinetic parameters of voriconazole. We should base on CYP2C19 gene polymorphism to guide the reasonable application of voriconazole during the clinical applications.