The Association Of Gene Polymorphism,Pharmacokinetics And Pharmacodynamics Of Amlodipine In Chinese Patients With Mild To Moderate Essential Hypertension

Objective(1) To investigate the pharmacokinetic characteristics, efficacy of amlodipine among different genotype and the Correlation between them.(2) Develop a population pharmacokinetics model for Amlodipine in Chinese patients with mild to moderate Essential Hypertension to investigate the effect of other factors on pharmacokinetic characteristics of amlodipine.Methods:Subjects were randomized from patients with mild to moderate Essential Hypertension (Age:40～75). After one-week washout period, they were administrated amlodipine for5mg/d,4weeks. Collect the plasma samples of the Oh and2h,6h,24h after28th dosing, also, collect blood pressure, demographic, physiological and biochemical data before and after treatment. Polymerase chain reaction(PCR) products were used to sequencing for genotyping of POR A503V (C>T),CYP3A4*1G(G>A), CYP3A5*3(A>G), MDR1C3435T(C>T) mutations. Plasma concentrations of amlodipine were measured by HPLC-MS/MS. The statistical analysis was performed with SPSS18.0while Nonlinear mixed-effects modelling was used to evaluate the data and develop a population pharmacokinetics model for amlodipine.Results:1112subjects were randomized and after washout period,81subjects entered into treating period.64subjects finished the trial and60taked parts in the pharmacokinetics study. The efficient of amldipine was65.6%in64patients who completed the experiment. After4-week treatment, the reduction of diastolic blood pressure(ΔDBP) was7.10±5.89mmHg while systolic blood pressure(ΔSBP) was (17.58±9.73) mmHg. The steady-state concentration in28th dosing (C0) was (7.31±3.34)ng/mL. The plasma concentration of2h,6h,24h after dosing were (8.89±4.10) ng/mL,(10.79±4.60) ng/mL,(7.40±3.32) ng/mL. The drug concentration of effective group was higher than ineffective group, but it’s not significant(P>0.05). The concentration of female was obviously higher than male’s(P<0.01). The POR A503V and CYP3A5*3mutation induced the higher concentration, but it’s not significant(P>0.05). As multiple linear regression shown, MDR1C3435T and CYP3A4*1G mutation were correlated positively withΔDBP (P<0.05) while gender was correlated with ΔSBP (P<0.05). Gender, CYP3A4*1G mutation, total cholesterol, low-density lipoprotein cholesterol, urea and uric acid were correlated with drug concentration (P<0.05).2Gender and MDR1C3435T genotype were mixed in the PPK model. When the patients were male and their MDR1C3435T genotype were CC or CT,(CL/F)i=28.1·eηCLi; When the patients were male and their MDRl C3435T genotype were TT,(CL/F)i=1.64*28.1·eηCLi; When the patients were female and their MDRl C3435T genotype were CC or CT,(CL/F)i=0.703*28.1·eηCLi; When the patients were female and their MDRl C3435T genotype were TT,(CL/F)i=1.64*0.703*28.1·eηCLi. When the patients’ MDR1C3435T genotype were CC or CT,(V/F)i=671·eηVi; When the patients’ MDRl C3435T genotype were TT,(V/F)i=3.07*671·eηVi.Conclusions:1The efficacy and safety of amlodipine in this study were consistent with literature.2The pharmacodynamics may correlate with pharmacokinetics of amlodipine, but the difference caused by pharmacokinetics was not obvious within a certain range.3Female reached higher amlodipine concentrations and lower oral clearance, but the pharmacodynamics was no significant difference.4The oral clearance of MDR13435TT was higher than CC and CT.5The mutation of POR A503V and CYP3A5*3can induce higher plasma concentration of amlodipine, but there’s no significant difference. 6The mutation of CYP3A4*1G can induce lower plasma concentration of amlodipine, but there’s no significant difference.7The building modeling was stable and credible so can be used to individuative administration of amlodipine.