Effect Of IL-10,PXR And CYP3A4 Polymorphisms On The Pharmacokinetics Of Amlodipine In Healthy Chinese Subjects

Background: Amlodipine is mainly metabolized by CYP3A4 in the liver.The expression of CYP3A4 is regulated by transcription factors such as the pregnionane X receptor?PXR?.And the expression of PXR was correlated with the expression level of IL-10.The expression of CYP3A4,PXR,and Il^-10 is genetic polymorphism The individual differences in the clinical efficacy of aminoclodipine were associated with the genetic polymorphism of CYP3A4,PXR,and il^-10 is worthy of further study.Objective:To investigate the effect of IL-10,PXR and CYP3A4 polymorphisms on amlodipine pharmacokinetic characteristic in healthy Chinese subjects.Method:1.43 healthy subjests were enrolled for the clinical trial of amlodipine,among which22 subjects were administered 10 mg orally under fasted conditions which the rest 21 subjects were administered 10 mg orally under fed conditions.The LC-MS method was established for the determination of amlodipine concentration in plasma.The DAS2.1 software was employed to calculate the pharmacokinetics.2.Genomic DNA was isolated from peripheral leukocytes and subjected to polymerase chain reaction?PCR?amplification,followed by PCR-RFLP,however Nine SNPs were designed for this research,IL-10?1082 G>A,819 C>T,592C>A?PXR?24381A>C,3'-UTR 10719G>A,3'-UTR 11193T>C?,CYP3A4(13989A>G,15820C>G,A₁₇₇₇₆,A insertion),were identified as the tag SNPs to represent the overall genetic polymorphic profile of IL-10,PXR,CYP3A4.To evaluate the potential functional change of these nine SNPs.Results: 1.The SNPs of IL-10-1082G>A,5 subjects obtained an 11.6% mutation frequency on its choosen Single Nucleotide Polymorphism site,IL-10-819C>T SNP site 10 out of the 43 subjects contained a mutation on position-819C>T with a23.20% mutation frequency and IL-10-592 C>A SNP site with a combined mutation of 18.60%.PXR?Exon1-24381A>C?loci?A>C?mutation frequency was 27.9%,?3'-UTR-10719 G>A?sites of mutation frequency was 18.6%),?3'UTR-11193T>C?loci?T>C?mutation frequency is 25.5%;CYP3A4??Exon 5?13989A>G?loci?A>G? mutation frequency was 16.5%,of CYP3A4?Exon 7?15820C/G)loci?C/G?mutation frequency was 20.9%,of CYP3A4(?Exon 9?A₁₇₇₇₆ A insertion)loci(A₁₇₇₇₆)mutation frequency was 11.6%.Interleukin 10?interleukin-10,IL-10?.The pharmacokinetic parameters including C_max,AUC and t_1/2 have no significant difference among the IL-10,PXR and CYP3A4 genotype groups.2.A high-fat high-calorie diets of amlodipine in healthy volunteers in China have obvious role in promoting the absorption of degree,fasting and postprandial AUC_0-t :212.09±40.53 ng·hml^-1 vs 291.20±92.02 ng·hml^-1?P<0.05?,AUC_0-?:228.56±52.37 ng·hml^-1 vs 313.209±103.471 ng·hml^-1?P<0.05??Conclusion: 1.Our study results demonstrated the polymorphisms of IL-10,PXR,CYP3A4 have no significant effect on the pharmacokinetics of amlodipine in healthy Chinese subjects 2.high-fat and high-calorie diet will enhance the absorbance of amlodipine.