超高效液相色谱-三重四极杆复合线性离子阱质谱法同时测定指印中36种降压药

doi:10.3724/SP.J.1123.2021.05012

摘要/Abstract

摘要：

指印中蕴含着供体摄入成分等相关信息,通过对其分析可对供体进行特征刻画,从而为案件侦查提供线索,指印分析也可用于药物摄入的定性检测,因此检验指印中的降压药具有重要的实际应用价值。建立了超高效液相色谱-三重四极杆复合线性离子阱质谱(UPLC-Q-TRAP/MS)同时检测指印中36种降压药的方法。前处理方法采用沉淀蛋白法,使用3×3 cm滤纸采集指印,将滤纸剪碎置于2 mL塑料离心管中,加入0.50 mL甲醇,涡旋混合1 min,超声振荡3 min,取出后以12000 r/min离心5 min,取上清液进样分析。采用ACQUITY UPLC^® BEH C18柱(100 mm×3.0 mm, 1.7 μm)分离,以0.01%甲酸水溶液和甲醇作为流动相进行梯度洗脱。质谱分析采用可编程多反应监测-信息关联采集-增强子离子(SMRM-IDA-EPI)扫描方式,在高灵敏度分析的同时进行二级谱库检索,增加定性结果的准确性。36种药物在0.05~50.00 ng/fingerprint范围内线性关系良好,相关系数(r)大于0.99,检出限和定量限分别为0.001~0.045 ng/fingerprint和0.002~0.050 ng/fingerprint,在0.25、2.50、25.00 ng/fingerprint 3个加标水平下的基质效应为79.0%~119.2%,回收率为79.3%~116.2%,日内精密度为0.2%~18.3%,日间精密度为1.6%~19.1%。使用该方法检测了87名高血压患者指印中的降压药,大部分样本中可检出其所服用的药物。该方法操作简单,灵敏度高,选择性好,适用于指印中降压药的筛查检验。

关键词: 超高效液相色谱-三重四极杆复合线性离子阱质谱, 降压药, 指印

Abstract:

Fingerprints contain important information such as the ingredients ingested by the donor. By analyzing the characteristic components in fingerprints, the donor can be characterized, which would provide insights for investigation of a given case. This approach can also be used in the qualitative monitoring of drug intake. Therefore, the examination of hypotensive drugs in fingerprints has significant value in practical application. This study established a method based on ultra performance liquid chromatography-triple quadrupole composite linear ion trap mass spectrometry (UPLC-Q-TRAP/MS) for the simultaneous determination of 36 hypotensive drugs in fingerprints. The pre-treatment method was based on protein precipitation. A 3×3 cm filter paper was cut into pieces and placed in a 2 mL plastic centrifuge tube after fingerprint collection. Then, 0.50 mL methanol was added, followed by vortex mixing for 1 min and ultrasonic oscillation for 3 min. The filter paper was centrifuged at 12000 r/min for 5 min, and the supernatant was withdrawn for sample analysis. An ACQUITY UPLC^® BEH C18 chromatographic column (100 mm×3.0 mm, 1.7 μm) was selected, with 0.01% aqueous formic acid and methanol as mobile phases for gradient elution. MS analysis involved scheduled multiple reaction monitoring-information dependent acquisition-enhanced product ion (SMRM-IDA-EPI) scanning. This method could be used to retrieve library researching during high-sensitivity analysis, which could increase the accuracy of qualitative results. The calibration curves showed good linearity in the range of 0.05-50.00 ng/fingerprint, with correlation coefficients (r) greater than 0.99 for all 36 analytes. The limits of detection and limits of quantification of the 36 hypotensive drugs were 0.001-0.045 ng/fingerprint and 0.002-0.050 ng/fingerprint, respectively. At spiked levels of 0.25, 2.50, 25.00 ng/fingerprint, the matrix effects, recoveries, intra-day precisions, and inter-day precisions of the 36 hypotensive drugs were 79.0%-119.2%, 79.3%-116.2%, 0.2%-18.3%, and 1.6%-19.1%, respectively. This method was used to detect hypotensive drugs in the fingerprints of 87 hypertensive patients, and hypotensive drug intakes were accurately detected in most cases. The established method is operationally simple, with high sensitivity and good selectivity, and it is suitable for screening and testing hypotensive drugs in fingerprints.

Key words: ultra performance liquid chromatography-triple quadrupole composite linear ion trap mass spectrometry (UPLC-Q-TRAP/MS), hypotensive drugs, fingerprints

中图分类号:

O658

杜秋瑶, 张云峰, 王继芬, 赵鹏, 吴小军, 董林沛, 李佳宜, 刘冰洁. 超高效液相色谱-三重四极杆复合线性离子阱质谱法同时测定指印中36种降压药[J]. 色谱, 2022, 40(2): 182-189.

DU Qiuyao, ZHANG Yunfeng, WANG Jifen, ZHAO Peng, WU Xiaojun, DONG Linpei, LI Jiayi, LIU Bingjie. Simultaneous determination of 36 hypotensive drugs in fingerprints by ultra performance liquid chromatography-triple quadrupole composite linear ion trap mass spectrometry[J]. Chinese Journal of Chromatography, 2022, 40(2): 182-189.

图/表 5

参考文献

[1]	Phan K, Barash M, Spindler X, et al. Int J Legal Med, 2020, 134(1):21
[2]	Lees H, Zapata F, Vaher M, et al. Sci Justice, 2018, 58(6):415
[3]	Alaoui I M, Halamek J. J Forensic Sci, 2019, 64(5):1495
[4]	Dam A V, Weert A V, Falkena K, et al. Anal Methods, 2018, 10(12):1413
[5]	Andrés A S, Barea J A, Rivaldería N, et al. Sci Justice, 2018, 58(5):323
[6]	Du Q Y, Dong L P, Wu X J, et al. Chemical Research and Application, 2020, 32(1):1
[6]	杜秋瑶, 董林沛, 吴小军, 等. 化学研究与应用, 2020, 32(1):1
[7]	Du Q, Zhang Y, Wang J, et al. J Chromatogr B, 2021, 1175:122496
[8]	Ismail M, Stevenson D, Costa C, et al. Clin Chem, 2018, 64(6):909
[9]	Hudson M, Stuchinskaya T, Ramma S, et al. J Anal Toxicol, 2019, 43(2):88
[10]	Maike S C, Petra H. J Chromatogr B, 2015, 997:218
[11]	Zheng X, Cui X G, Jiang J. The Chinese Journal of Clinical Pharmacology, 2018, 34(10):1155
[11]	郑昕, 崔馨戈, 江骥. 中国临床药理学杂志, 2018, 34(10):1155
[12]	Banas A M, Banas K, Lo M K F, et al. Anal Chem, 2020, 92(14):9649
[13]	Zheng L N, Ma R L, Li Q, et al. Anal Bioanal Chem, 2019, 411(18):4151
[14]	Hazarika P, Jickells S M, Wolff K, et al. Anal Chem, 2010, 82(22):9150
[15]	Zhou J, Zhao G, Lu W, et al. Nano, 2019, 14(2):1950026
[16]	You W, Zhao Y B, Sun J, et al. Chinese Journal of Applied Chemistry, 2021, 38(4):376
[16]	游伟, 赵雅彬, 孙婧, 等. 应用化学, 2021, 38(4):376
[17]	Dorakumbura B N, Busetti F, Lewis S W. Forensic Chem, 2020, 17:100193
[18]	Helmond W V, Herwijnen A W V, Riemsdijk J J H V, et al. Forensic Chem, 2019, 16:100183
[19]	Cai L, Xia M C, Wang Z, et al. Anal Chem, 2017, 89(16):8372
[20]	Zhao Z, Shen J, Wang M. Nanotechnology, 2020, 31(14):145504
[21]	Lin Q, Yang C, Li M L, et al. Chinese Journal of Chromatography, 2021, 39(4):399
[21]	林强, 杨超, 李美丽, 等. 色谱, 2021, 39(4):399
[22]	Cheng Q, Shou L, Chen C, et al. J Chromatogr B, 2017, 1064:92
[23]	Mueller C A, Weinmann W, Dresen S, et al. Rapid Commun Mass Sp, 2005, 19(10):1332
[24]	Li X, Wang M, Zhao J, et al. J Pharmaceut Biomed, 2019, 166:213
[25]	Huang J, Bathena S P R, Alnouti Y, et al. Drug Metab Pharmacokinet, 2010, 25(5):487
[26]	Lü Y F, Wang J F, Chang J, et al. Chinese Journal of Chromatography, 2019, 37(1):80
[26]	吕昱帆, 王继芬, 常靖, 等. 色谱, 2019, 37(1):80
[27]	Jacob S, Jickells S, Wolff K, et al. Drug Metab Lett, 2008, 2(4):245

No.	Compound	t_R/min	Precursor ion/(m/z)	Product ions/(m/z)	CE/eV	DP/V
1	atenolol (阿替洛尔)	3.08	267.2	190.2, 145.1^*	24, 32	80
2	hydrochlorothiazide (氢氯噻嗪)	3.19	296.0	268.9^*, 205.0	-26, -30	-60
3	lisinopril (赖诺普利)	3.71	406.2	246.0, 84.2^*	30, 29	80
4	triamterene (氨苯蝶啶)	3.77	254.2	237.2^*, 104.1	34, 48	80
5	metoprolol (美托洛尔)	4.03	268.2	116.1^*, 98.1	22, 24	80
6	captopril (卡托普利)	4.22	216.0	182.0^*, 114.1	-15, -16	-50
7	chlortalidone (氯噻酮)	4.23	337.0	190.1^*, 146.1	-22, -23	-80
8	bisoprolol (比索洛尔)	4.58	326.3	116.2^*, 74.1	24, 28	80
9	olmesartan (奥美沙坦)	4.66	447.2	429.2, 207.1^*	15, 26	60
10	propranolol (普萘洛尔)	4.81	260.2	183.1, 116.1^*	23, 22	80
11	carvedilol (卡维地洛)	4.89	407.3	224.1^*, 99.9	28, 32	80
12	enalapril (依那普利)	4.90	377.2	303.2, 234.2^*	25, 24	80
13	furosemide (呋塞米)	4.90	329.0	285.0, 205.0^*	-20, -28	-60
14	betaxolol (倍他洛尔)	4.92	308.3	116.1^*, 98.0	25, 30	80
15	imidapril (咪达普利)	4.93	406.2	332.1, 234.2^*	24, 25	80
16	eplerenone (依普利酮)	4.99	415.2	337.2, 163.0^*	20, 20	80
17	verapamil (维拉帕米)	4.99	455.2	303.1, 165.0^*	31, 34	80
18	nicardipine (尼卡地平)	5.05	480.3	315.2^*, 166.0	28, 23	80
19	indapamide (吲达帕胺)	5.07	366.0	132.1^*, 91.0	16, 38	22
20	perindopril (培哚普利)	5.14	369.3	172.1^*, 98.1	26, 43	80
21	benidipine (贝尼地平)	5.16	506.3	315.2, 174.2^*	31, 30	80
22	benazepril (贝那普利)	5.40	425.4	351.1^*, 190.0	27, 39	80
23	ramipril (雷米普利)	5.52	417.2	234.2^*, 130.1	25, 35	80
24	amlodipine (氨氯地平)	5.56	409.2	294.0, 238.0^*	11, 11	80
25	telmisartan (替米沙坦)	5.59	515.4	497.2, 276.2^*	45, 58	80
26	nifedipine (硝苯地平)	5.62	329.3	284.1^*, 267.9	27, 30	50
27	candesartan (坎地沙坦)	5.71	441.2	423.2, 263.1^*	14, 15	60
28	losartan (氯沙坦)	5.84	435.2	391.3, 157.1^*	-18, -28	-60
29	lercanidipine (乐卡地平)	5.94	611.8	280.0^*, 100.0	29, 50	80
30	irbesartan (厄贝沙坦)	5.97	427.2	399.3, 193.0^*	-25, -32	-60
31	spironolactone (螺内酯)	6.02	417.3	341.3^*, 106.9	13, 41	60
32	valsartan (缬沙坦)	6.13	433.9	350.1, 179.2^*	-24, -29	-80
33	nitrendipine (尼群地平)	6.27	361.3	329.2, 315.2^*	14, 15	80
34	felodipine (非洛地平)	6.96	382.1	236.1, 144.9^*	-15, -16	-80
35	lacidipine (拉西地平)	7.30	473.4	354.1^*, 310.1	17, 31	40
36	fosinopril (福辛普利)	7.51	564.4	436.3, 152.2^*	20, 51	80

No.	Compound	t_R/min	Precursor ion/(m/z)	Product ions/(m/z)	CE/eV	DP/V
1	atenolol (阿替洛尔)	3.08	267.2	190.2, 145.1^*	24, 32	80
2	hydrochlorothiazide (氢氯噻嗪)	3.19	296.0	268.9^*, 205.0	-26, -30	-60
3	lisinopril (赖诺普利)	3.71	406.2	246.0, 84.2^*	30, 29	80
4	triamterene (氨苯蝶啶)	3.77	254.2	237.2^*, 104.1	34, 48	80
5	metoprolol (美托洛尔)	4.03	268.2	116.1^*, 98.1	22, 24	80
6	captopril (卡托普利)	4.22	216.0	182.0^*, 114.1	-15, -16	-50
7	chlortalidone (氯噻酮)	4.23	337.0	190.1^*, 146.1	-22, -23	-80
8	bisoprolol (比索洛尔)	4.58	326.3	116.2^*, 74.1	24, 28	80
9	olmesartan (奥美沙坦)	4.66	447.2	429.2, 207.1^*	15, 26	60
10	propranolol (普萘洛尔)	4.81	260.2	183.1, 116.1^*	23, 22	80
11	carvedilol (卡维地洛)	4.89	407.3	224.1^*, 99.9	28, 32	80
12	enalapril (依那普利)	4.90	377.2	303.2, 234.2^*	25, 24	80
13	furosemide (呋塞米)	4.90	329.0	285.0, 205.0^*	-20, -28	-60
14	betaxolol (倍他洛尔)	4.92	308.3	116.1^*, 98.0	25, 30	80
15	imidapril (咪达普利)	4.93	406.2	332.1, 234.2^*	24, 25	80
16	eplerenone (依普利酮)	4.99	415.2	337.2, 163.0^*	20, 20	80
17	verapamil (维拉帕米)	4.99	455.2	303.1, 165.0^*	31, 34	80
18	nicardipine (尼卡地平)	5.05	480.3	315.2^*, 166.0	28, 23	80
19	indapamide (吲达帕胺)	5.07	366.0	132.1^*, 91.0	16, 38	22
20	perindopril (培哚普利)	5.14	369.3	172.1^*, 98.1	26, 43	80
21	benidipine (贝尼地平)	5.16	506.3	315.2, 174.2^*	31, 30	80
22	benazepril (贝那普利)	5.40	425.4	351.1^*, 190.0	27, 39	80
23	ramipril (雷米普利)	5.52	417.2	234.2^*, 130.1	25, 35	80
24	amlodipine (氨氯地平)	5.56	409.2	294.0, 238.0^*	11, 11	80
25	telmisartan (替米沙坦)	5.59	515.4	497.2, 276.2^*	45, 58	80
26	nifedipine (硝苯地平)	5.62	329.3	284.1^*, 267.9	27, 30	50
27	candesartan (坎地沙坦)	5.71	441.2	423.2, 263.1^*	14, 15	60
28	losartan (氯沙坦)	5.84	435.2	391.3, 157.1^*	-18, -28	-60
29	lercanidipine (乐卡地平)	5.94	611.8	280.0^*, 100.0	29, 50	80
30	irbesartan (厄贝沙坦)	5.97	427.2	399.3, 193.0^*	-25, -32	-60
31	spironolactone (螺内酯)	6.02	417.3	341.3^*, 106.9	13, 41	60
32	valsartan (缬沙坦)	6.13	433.9	350.1, 179.2^*	-24, -29	-80
33	nitrendipine (尼群地平)	6.27	361.3	329.2, 315.2^*	14, 15	80
34	felodipine (非洛地平)	6.96	382.1	236.1, 144.9^*	-15, -16	-80
35	lacidipine (拉西地平)	7.30	473.4	354.1^*, 310.1	17, 31	40
36	fosinopril (福辛普利)	7.51	564.4	436.3, 152.2^*	20, 51	80

Compound	Regression equation	r	LOD/(ng/fingerprint)	LOQ/(ng/fingerprint)
Atenolol	y=9.05×10⁴ x+2.50×10⁴	0.9950	0.014	0.048
Hydrochlorothiazide	y=4.05×10⁴ x+3.15×10³	0.9993	0.001	0.003
Lisinopril	y=1.26×10⁴ x+2.24×10⁴	0.9958	0.045	0.050
Triamterene	y=5.39×10⁵ x+5.69×10³	0.9958	0.001	0.004
Metoprolol	y=1.48×10⁵ x+2.56×10⁴	0.9979	0.003	0.011
Captopril	y=1.06×10⁴ x+1.70×10⁴	0.9903	0.035	0.050
Chlortalidone	y=3.62×10⁴ x+4.49×10³	0.9979	0.007	0.022
Bisoprolol	y=2.23×10⁵ x+6.91×10⁴	0.9982	0.001	0.002
Olmesartan	y=2.95×10⁵ x+4.33×10⁴	0.9988	0.004	0.014
Propranolol	y=3.27×10⁵ x+1.61×10⁵	0.9960	0.001	0.005
Carvedilol	y=3.60×10⁵ x+1.54×10⁵	0.9964	0.002	0.007
Enalapril	y=1.89×10⁵ x+3.08×10⁴	0.9992	0.001	0.007
Furosemide	y=8.57×10⁴ x+1.54×10⁴	0.9982	0.026	0.050
Betaxolol	y=1.67×10⁵ x+7.48×10⁴	0.9970	0.002	0.007
Imidapril	y=1.14×10⁵ x+1.29×10⁴	0.9987	0.003	0.011
Eplerenone	y=3.96×10⁴ x+4.69×10³	0.9996	0.004	0.013
Verapamil	y=2.12×10⁵ x+5.59×10⁴	0.9980	0.001	0.003
Nicardipine	y=5.07×10⁵ x+3.14×10⁵	0.9948	0.001	0.003
Indapamide	y=6.05×10⁴ x+9.59×10³	0.9988	0.003	0.010
Perindopril	y=4.99×10⁵ x+1.40×10⁵	0.9983	0.001	0.003
Benidipine	y=4.97×10⁵ x+2.41×10⁵	0.9964	0.001	0.005
Benazepril	y=3.09×10⁵ x+3.52×10⁴	0.9990	0.002	0.007
Ramipril	y=3.03×10⁵ x+7.46×10⁴	0.9986	0.001	0.004
Amlodipine	y=1.96×10⁵ x+1.79×10⁴	0.9987	0.007	0.022
Telmisartan	y=6.30×10⁵ x+4.02×10⁵	0.9952	0.002	0.005
Nifedipine	y=2.05×10⁵ x+1.68×10⁴	0.9976	0.001	0.005
Candesartan	y=1.33×10⁵ x+6.37×10³	0.9993	0.002	0.007
Losartan	y=1.39×10⁵ x+5.19×10³	0.9989	0.009	0.030
Lercanidipine	y=8.45×10⁴ x+3.97×10⁴	0.9967	0.004	0.014
Irbesartan	y=3.29×10⁴ x+8.70×10³	0.9984	0.008	0.027
Spironolactone	y=1.16×10⁵ x+4.92×10⁴	0.9993	0.005	0.018
Valsartan	y=5.08×10⁴ x+3.65×10³	0.9992	0.005	0.018
Nitrendipine	y=3.38×10⁵ x+1.27×10⁵	0.9976	0.006	0.019
Felodipine	y=4.77×10⁴ x+1.13×10⁴	0.9960	0.003	0.009
Lacidipine	y=2.24×10⁵ x+3.71×10⁴	0.9937	0.001	0.004
Fosinopril	y=3.12×10⁴ x+6.59×10³	0.9902	0.005	0.017

Compound	Regression equation	r	LOD/(ng/fingerprint)	LOQ/(ng/fingerprint)
Atenolol	y=9.05×10⁴ x+2.50×10⁴	0.9950	0.014	0.048
Hydrochlorothiazide	y=4.05×10⁴ x+3.15×10³	0.9993	0.001	0.003
Lisinopril	y=1.26×10⁴ x+2.24×10⁴	0.9958	0.045	0.050
Triamterene	y=5.39×10⁵ x+5.69×10³	0.9958	0.001	0.004
Metoprolol	y=1.48×10⁵ x+2.56×10⁴	0.9979	0.003	0.011
Captopril	y=1.06×10⁴ x+1.70×10⁴	0.9903	0.035	0.050
Chlortalidone	y=3.62×10⁴ x+4.49×10³	0.9979	0.007	0.022
Bisoprolol	y=2.23×10⁵ x+6.91×10⁴	0.9982	0.001	0.002
Olmesartan	y=2.95×10⁵ x+4.33×10⁴	0.9988	0.004	0.014
Propranolol	y=3.27×10⁵ x+1.61×10⁵	0.9960	0.001	0.005
Carvedilol	y=3.60×10⁵ x+1.54×10⁵	0.9964	0.002	0.007
Enalapril	y=1.89×10⁵ x+3.08×10⁴	0.9992	0.001	0.007
Furosemide	y=8.57×10⁴ x+1.54×10⁴	0.9982	0.026	0.050
Betaxolol	y=1.67×10⁵ x+7.48×10⁴	0.9970	0.002	0.007
Imidapril	y=1.14×10⁵ x+1.29×10⁴	0.9987	0.003	0.011
Eplerenone	y=3.96×10⁴ x+4.69×10³	0.9996	0.004	0.013
Verapamil	y=2.12×10⁵ x+5.59×10⁴	0.9980	0.001	0.003
Nicardipine	y=5.07×10⁵ x+3.14×10⁵	0.9948	0.001	0.003
Indapamide	y=6.05×10⁴ x+9.59×10³	0.9988	0.003	0.010
Perindopril	y=4.99×10⁵ x+1.40×10⁵	0.9983	0.001	0.003
Benidipine	y=4.97×10⁵ x+2.41×10⁵	0.9964	0.001	0.005
Benazepril	y=3.09×10⁵ x+3.52×10⁴	0.9990	0.002	0.007
Ramipril	y=3.03×10⁵ x+7.46×10⁴	0.9986	0.001	0.004
Amlodipine	y=1.96×10⁵ x+1.79×10⁴	0.9987	0.007	0.022
Telmisartan	y=6.30×10⁵ x+4.02×10⁵	0.9952	0.002	0.005
Nifedipine	y=2.05×10⁵ x+1.68×10⁴	0.9976	0.001	0.005
Candesartan	y=1.33×10⁵ x+6.37×10³	0.9993	0.002	0.007
Losartan	y=1.39×10⁵ x+5.19×10³	0.9989	0.009	0.030
Lercanidipine	y=8.45×10⁴ x+3.97×10⁴	0.9967	0.004	0.014
Irbesartan	y=3.29×10⁴ x+8.70×10³	0.9984	0.008	0.027
Spironolactone	y=1.16×10⁵ x+4.92×10⁴	0.9993	0.005	0.018
Valsartan	y=5.08×10⁴ x+3.65×10³	0.9992	0.005	0.018
Nitrendipine	y=3.38×10⁵ x+1.27×10⁵	0.9976	0.006	0.019
Felodipine	y=4.77×10⁴ x+1.13×10⁴	0.9960	0.003	0.009
Lacidipine	y=2.24×10⁵ x+3.71×10⁴	0.9937	0.001	0.004
Fosinopril	y=3.12×10⁴ x+6.59×10³	0.9902	0.005	0.017

Compound	Matrix effects/%			Recoveries/%			Intra-day RSDs/%			Inter-day RSDs/%
Compound	0.25 ng/fp	2.50 ng/fp	25.00 ng/fp	0.25 ng/fp	2.50 ng/fp	25.00 ng/fp	0.25 ng/fp	2.50 ng/fp	25.00 ng/fp	0.25 ng/fp	2.50 ng/fp	25.00 ng/fp
Atenolol	119.2	106.6	105.4	84.7	91.5	82.9	18.0	13.0	3.7	17.4	13.9	12.5
Hydrochlorothiazide	81.5	83.8	86.8	95.8	83.7	83.3	4.4	4.1	0.6	5.1	3.5	2.5
Lisinopril	114.1	114.4	115.1	81.4	81.4	80.5	5.2	2.7	3.6	6.2	3.2	4.3
Triamterene	99.5	95.5	94.7	80.7	81.8	79.3	10.2	9.6	9.6	9.6	8.5	9.1
Metoprolol	93.0	96.0	93.1	97.8	106.1	92.3	2.7	3.6	5.3	3.5	3.1	5.7
Captopril	81.9	82.3	85.7	80.1	114.3	83.5	18.3	15.6	13.6	14.6	14.2	12.7
Chlortalidone	87.1	98.3	98.7	85.4	97.8	95.8	1.7	4.9	6.4	2.9	3.7	5.0
Bisoprolol	92.2	93.5	99.8	94.8	99.9	100.0	1.4	1.6	2.1	3.6	2.3	2.2
Olmesartan	92.3	114.2	95.9	84.9	98.6	94.6	1.5	3.2	2.9	2.9	3.9	3.5
Propranolol	88.6	99.2	96.0	92.2	106.9	89.9	2.0	4.9	5.5	3.2	3.4	4.5
Carvedilol	90.5	96.5	100.9	83.1	83.1	80.9	5.5	5.0	4.0	7.5	4.9	6.2
Enalapril	90.5	90.7	101.1	88.1	100.4	95.4	4.8	2.1	2.2	4.8	4.3	2.2
Furosemide	97.0	93.5	105.6	82.2	81.3	83.0	10.4	10.6	4.0	8.8	8.4	3.5
Betaxolol	95.2	87.0	95.8	87.9	107.2	98.6	1.9	1.6	3.4	4.1	3.3	4.9
Imidapril	88.8	95.7	95.4	83.2	93.0	89.4	5.5	3.6	3.9	4.3	3.7	5.1
Eplerenone	97.4	86.0	100.5	84.9	96.6	93.2	1.4	4.0	1.0	3.1	4.1	4.1
Verapamil	95.0	94.8	94.2	98.9	98.3	102.0	2.3	3.7	1.1	3.0	3.0	5.7
Nicardipine	93.3	97.8	82.0	84.8	95.2	92.1	2.3	1.8	2.7	3.1	2.6	4.1
Indapamide	95.2	99.8	94.4	83.0	85.4	100.1	1.4	0.8	2.3	4.5	4.2	4.2
Perindopril	94.8	94.1	99.3	86.9	101.3	100.6	2.6	2.8	1.4	3.3	3.4	2.1
Benidipine	91.3	96.4	92.0	80.5	102.9	100.3	2.0	3.5	2.7	1.6	3.2	3.2
Benazepril	90.9	90.4	103.9	89.0	81.7	87.9	3.0	4.3	2.7	3.0	4.9	2.7
Ramipril	90.5	94.6	100.6	96.3	98.9	97.9	2.2	3.1	1.9	2.8	4.9	3.0
Amlodipine	94.1	87.8	93.9	79.4	92.9	84.3	5.3	1.0	5.0	6.0	4.1	5.2
Telmisartan	89.2	88.7	98.4	91.0	102.6	94.7	0.2	3.2	2.2	6.1	5.1	3.7
Nifedipine	82.7	82.5	93.9	80.4	84.3	81.1	9.5	5.2	2.8	7.0	7.5	4.6
Candesartan	87.6	113.5	95.4	116.2	94.1	92.6	5.0	6.9	1.7	7.5	7.5	3.7
Losartan	83.9	97.4	113.7	79.3	93.8	96.3	5.1	6.3	3.7	4.6	5.4	4.7
Lercanidipine	90.9	81.6	87.1	86.7	111.1	104.0	5.1	3.4	5.2	7.3	7.7	5.7
Irbesartan	85.0	88.9	104.1	93.6	96.7	100.9	1.7	1.0	1.5	3.2	4.0	4.7
Spironolactone	102.9	104.1	109.1	110.7	97.5	95.5	12.7	6.5	9.7	13.4	19.1	13.5
Valsartan	79.0	114.4	105.4	103.5	113.3	102.1	4.3	8.9	1.2	5.8	7.7	3.5
Nitrendipine	92.0	86.2	95.2	85.1	94.9	97.7	5.6	5.3	5.9	10.1	9.4	6.5
Felodipine	104.6	100.8	98.4	80.9	97.1	84.4	1.2	10.0	5.5	5.7	8.9	7.8
Lacidipine	81.7	85.0	100.9	80.6	86.5	91.8	6.1	7.0	9.9	8.6	4.4	7.4
Fosinopril	103.8	105.1	106.5	105.0	87.5	82.2	14.0	11.2	13.9	15.5	17.0	12.5