基因多型性與Nifedipine及Barnidipine的血中濃度及降壓效果之相關性研究

Abstract

研究背景 為研究nifedipine與barnidipine兩種鈣離子通道拮抗劑，常用為降血壓藥，對於在CYP 3A4、CYP 3A5、Ca2+ channel基因上帶有不同SNP (Single nucleotide polymorphism)的病人在藥物代謝及降血壓效果上是否有不同的表現，而設計此研究。 研究方法 Nifedipine組及barnidipine組各收20個病人，在基準日（D0）、第四週（W4）、第八週（W8）及第十二週（W12）測量病人血壓值及心跳頻率，作為藥物療效評估統計分析之用。 利用HPLC測藥物血中濃度，在臨床試驗第四週（W4）及第十二週（W12）抽血10 c.c.供檢測血中濃度。 利用SNPstream鑑定病人基因型，主要包括三個基因的SNP：CYP 3A4、CYP3A5及Ca2+ channel的Cav 1.2。 本臨床試驗通過台大醫院倫理委員會同意，案號941227。 研究結果 Nifedipine組20個病人在服藥後十二週內的血壓收縮壓值只有1位高於JNC VII建議的140 mmHg，其餘病人皆在建議值內，而且nifedipine對收縮壓的降壓效果比舒張壓顯著。 Barnidipine組20個病人在服藥後十二週內的血壓收縮壓值有3位高於JNC VII建議的140 mmHg，其餘病人皆在建議值內，且barnidipine對收縮壓及舒張壓的降壓效果無明顯差異。 Nifedipine藥物血中濃度第四週平均為59.80 ng/ml，第十二週平均為153.27 ng/ml。 進行基因型鑑定之SNP包括：CYP 3A4基因6個、CYP 3A5基因11個、Ca2+ channel的Cav 1.2基因5個。基因鑑定結果與NCBI dbSNP有出入，差異較大的SNP為CYP 3A4的rs2404955；CYP 3A5的rs4646450、rs3800959及Cav 1.2的rs1051375、rs216008、rs215976、rs2238032，這可能是人種不同及樣本數太小所導致。 Nifedipine組與barnidipine組服藥後十二週內血壓收縮壓值高於JNC VII建議值的病人，與血壓控制良好的病人基因型不同點在於：CYP 3A4的rs4646440為TC allele；CYP 3A5的rs4646457、rs4646450、rs776746、rs15524、rs4646456、rs4646453、rs4646449、rs4646447、rs4646446、rs1419745、rs3800959為heterozygous allele。 結論 Nifedipine及barnidipine對於大部分輕度及中度高血壓的病人皆有良好的血壓控制效果。其中nifedipine對於收縮壓有較好的控制。但是nifedipine的藥物血中濃度與降血壓效果之間的關係並不顯著，可能還有其他因素影響血壓。 如果病人的CYP 3A4的rs4646440為TC allele及本研究中CYP 3A5的SNP多為heterozygous allele，則nifedipine及barnidipine的降血壓效果可能會減弱，導致血壓控制無法達到預期目標。

Background This study is aimed to analyze the association of antihypertensive effects with particular SNPs of CYP 3A4, CYP 3A5 and Ca2+ channel. The drugs of interest are nifedipine and barnidipine which are Ca2+ channel blockers. Methods Twenty patients each are enrolled in nifedipine and barnidipine groups. Patients’ blood pressures and heart rates were measured at visits D0, W4, W8 and W12. Blood drawn was performed in patients receiving nifedipine or barnidipine at visits W4 and W12 and was subjected to HPLC. Particular SNPs of CYP 3A4, CYP 3A5 and Cav 1.2 of Ca2+ channel were identified by SNPstream. This clinical trial was approved by NTUHREC and issued a protocol ID 941227.

Results Systolic blood pressures in one out of twenty patients of nifedipine group were higher than the recommended value of JNC VII. Nifedipine was more effective in reduction of systolic blood pressure than that of diastolic blood pressure. Systolic blood pressures in three out of twenty patients of barnidipine group were higher than the recommended value of JNC VII. Reduction of systolic and diastolic blood pressures was equally effective in patients receiving barnidipine. The averaged plasma concentration of nifedipine was 59.80 ng/ml at W4 and 153.27 ng/ml at W12, respectively. Six SNPs of CYP 3A4, eleven SNPs of CYP 3A5 and five SNPs of Cav 1.2 were genotyped by SNPstream. Variant frequencies in certain SNPs were different from that collected in dbSNP. Racial and sample size factors might account for the differences. Patients with higher systolic blood pressure than the recommended value of JNC VII after treatment for twelve weeks carried T > C allele in SNP rs4646440 of CYP 3A4 and heterozygous alleles in rs4646457、rs4646450、rs776746、rs15524、rs4646456、rs4646453、rs4646449、rs4646447、rs4646446、rs1419745 and rs3800959 of CYP 3A5. Conclusion Nifedipine and barnidipine are effective antihypertensives for prehypertension and stage 1 hypertension. Nifedipine controls systolic blood pressure better than diastolic blood pressure. Plasma concentrations of nifedipine varied at visits W4 and W12, which was irrelevant to the reduction of blood pressure. Four patients are less responsive to nifedipine or barnidipine, carrying T > C allele at CYP 3A4 and carrying heterozygous alleles at 11 SNPs of CYP 3A5 in a high tendency manner.