The Correlation Study Of PXR Polymorphisms And Plasma Concentration And Its Antihypertensive Effect Of Amlodipine

Objective:1.To investigate the effect of pregnane X receptor (PXR) polymorphisms on pharmacokinetics of anlodipine in male healthy volunteers.2. To investigate the frequency of PXR 11156A> C,11193T> C,8055 C>T and PXR*1B (contain 11193T>C and 8055C＞T) in essential hypertension patients and further evaluate the association between PXR polymorphisms and the steady-state trough concentration and antihypertensive effect of amlodipine.Methods:1. Genotyping of PXR 11156A>C,11193T>C and 8055 C＞T were determined by pyrosequencing sequenator. PXR*1B was analyzed by PHASE V.2.1.19 male healthy volunteers, grouped by genotype, received a single oral dose of 5 mg amlodipine. Venous blood samples of 5 mL were drawn from forearm vein into EDTA tubes before(0h)and at2,3,4,5,6,8,10,12,24,48,72,96,108h, respectively, after amlodipine administration. Plasma was separated, and determined by high performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS). The pharmacokinetics of amlodipine was analyzed with DAS 2.0 software. Statistical analyses were performed by the SPSS 13.0 software for Windows.2.135 essential hypertension patients were randomly collected from Changsha of Hunan to investigate the frequency of PXR polymorphism. Pyrosequencing sequenator was applied to detect PXR11156A>C,11193T>C and 8055C＞T. PXR*1B was analyzed by PHASE V.2.1. 62 of those patients rolled the clinical trial. They were treated with amlodipine for 8 weeks, according to once a day,5 mg per time in every morning. Blood pressure was measured at 0,4,8-week. At 8-week the venous blood samples were collected before amlodipine administration. Plasma was used to determined concentration of amlodipine by HPLC-MS/MS. Statistical analyses were performed by the SPSS 13.0 software for Windows.Results:1. The mean pharmacokinetics of amlodipine is AUC0-108(288.0±83.2 ng·h·ml-1), AUC0-∞(311.8±93.0 ng·h·ml-1), T(?)(27.8±3.6 h), Tmax(5.8±2.1 h), CL/F(17.4±4.9 L·h-1), Cmax(8.3±2.3 ng·ml-1), respectively.2. The time to the peak plasma concentration was significantly lower in subjects with PXR11156AC/11193TC (4.8±1.5 h) than those in 11156CC/11193CC(7.8±3.1h)(P<0.05). The peak plasma concentrations were highest in subjects with 8055TT (11.1±1.6 ng·ml-1), lower in subjects with 8055CC (7.7±1.4 ng·ml-1) and 8055CT (7.8±2.3 ng·ml-1) (P＜0.05). AUC0-∞,AUC0-108,and Cmax of PXR*1B/*1B carries was 405.9±87.8 ng·h·ml-1,375.7±70.8 ng·h·ml-1, 11.1±1.6ng·ml-1, which is significantly higher than PXR*1B non-carriers (266.5±67.0 ng·h·ml-1,245.5±61.6 ng·h·ml-1,7.1±1.4ng·ml-1)(P<0.05), CL/F of PXR*1B/*1B carriers and PXR*1B non-carriers is 12.7±2.4 L·h-1 and 19.7±4.7 L·h-1 (P<0.05).3. PXR11156A>C was in complete linkage with 11193T>C. Of essential hypertension patients, the frequency of PXR11156C/11193C,8055 C>T,PXR*1B was 47.4%,44.8%and 39.2%, respectively.4.61 of patients finished the clinical trial and effective power of amlodipine is 63.9%. There was no significantly difference of the steady-state trough concentration and antihypertensive effect of amlodipine among genotypes of PXR11156A>C/11193T>C,8055 C >T and PXR*1B (P>0.05).Conclusion:1. PXR11156A＞C/1193T＞C,8055C＞T and PXR*1B can affect the pharmacokinetics of amlodipine in healthy volunteers to some extent.2. PXR polymorphisms didn't significantly affect the steady-state trough concentration and antihypertensive effect of amlodipine in essential hypertension patients.