Identification and Pharmacokinetics of Multiple Potential Bioactive Constituents after Oral Administration of Radix Astragali on Cyclophosphamide-Induced Immunosuppression in Balb/c Mice
Abstract
:1. Introduction
2. Results and Discussion
2.1. Identification of Compounds in RA Extract
No. | TR (min) | Formula | [M + H]+ (Error, ppm) | [M − H]− (Error, ppm) | Fragment Ions in Positive (+) Ion Mode | Fragment Ions in Negative (−) Ion Mode | Identification | Source | ||
---|---|---|---|---|---|---|---|---|---|---|
RA | Control Plasma | Dosed Plasma | ||||||||
1 | 0.96 | C6H12O6 | 179.0563 (+0.79) | 203.0521 [M + Na]+ (−2.4), 143.0327 [M + Na − C2H4O2]+ | - | Hexose | + | + | 0.25–36 h | |
2 | 0.97 | C4H8N2O3 | 133.0607 (−0.7) | 131.0472 (+7.6) | - | 114.0194 [M − H − NH3]−, 113.0354 [M − H − H2O]−, 95.0257 [M − H − CH2O2]− | Asparagine a | + | + | 1–36 h |
3 | 1.00 | C12H22O11 | - | 341.1089 (−0.08) | 365.1053 [M + Na]+ (−0.36), 203.0532 [M + Na − glc]+, 185.0425 [M + Na − C6H12O6]+ | 179.0553 [M − H − glc]− | Disaccharide | + | - | 0.25–4 h |
4 | 1.02 | C5H13NO | 104.1071 (1.0) | - | 60.0833 [M + H − C2H5O]+ | - | Choline a | + | + | 0.25–36 h |
5 | 1.05 | C4H9NO2 | 104.0706 (−0.1) | 102.0615 (+1.0) | - | - | γ-Aminobutyric acid a | + | + | 0.25–36 h |
6 | 1.12 | C18H32O16 | - | 503.1621 (+1.7) | 527.1583 [M + Na]+ (+0.1) | 161.0453 [M + H − 2glc]− | Raffinose a | + | - | 0.25–3 h |
7 | 1.21 | C5H5N5 | 136.0617 (−0.6) | 134.0473 (+1.0) | 119.0351 [M + H − NH3]+, 92.0248 [M + H − NH3 − HCN]+ | 107.0366 [M + H − HCN]+, 72.0186 | Adenine a | + | - | - |
8 | 1.37 | C6H5NO2 | 124.0393 (−0) | 106.0285 [M + H − H2O]+, 80.0500 [M + H − CO2]+, 78.0343, 53.0417 | - | Nicotinic acid a | + | 0.25–4 h | ||
9 | 1.63 | C6H13NO2 | 132.1018 (−1.0) | 130.0874 (+1.0) | 86.0975 [M + H − CH2O2]+, 69.0714 [M + H−NH3 − CH2O2]+ | - | Leucine a | + | + | 0.25–36 h |
10 | 1.86 | C10H13N5O4 | 268.1040 (−0.3) | 266.0899 (+0.7) | 136.0613 [M + H − ribose]+, 119.0347 [M + H − ribose − NH3]+ | 135.0315 [M − H − ribose]−, 107.0377 [M − H − C6 H12O5 − HCN]− | Adenine nucleoside a | + | + | 0.25–36 h |
11 | 2.60 | C9H11NO2 | 166.0864 (+1.0) | 164.0717 (−0.12) | 149.0588 [M + H − NH3]+, 131.0507 [M + H − NH3 − H2O]+, 120.0814 [M + H − CH2O2]+, 103.0550 [M + H − NH3 − CH2O2]+ | 147.0460 [M − H − NH3]−, 103.0571 [M − H − NH3 − CO2]−, | Phenylalanine a | + | + | 0.25–36 h |
12 | 3.70 | C7H6O4 | - | 153.0196 (+2.0) | - | 109.0293 [M − H − CO2]−, 81.0349 | Protocatechuic acid a | + | + | 0.25–36 h |
13 | 4.01 | C18H26O12 | - | 433.1355 (+0.9) | 457.1319 [M + Na]+ (+0.25) | 301.0939 [M − H − C5H8O4]−, 139.0399 [M − H − C5H8O4 − glc]−, 161.0454, 124.0168 | Markhamioside F | + | - | 0.25–8 h |
14 | 4.87 | C11H12N2O2 | 205.0970 (−0.25) | 203.0830 (+2) | 188.0704 [M + H − NH3]+, 170.0596 [M + H − NH3 − H2O]+, 159.0915 [M + H − CH2O2]+, 132.0806 [M + H − NH3 − CH2O2]+, 146.0600, 118.0652, 91.0553 | 185.0443 [M − H−NH3]−, 159.0916 [M − H−CO2]−, 142.0659 [M − H − NH3 − CO2]−, 116.0507, 74.0276 | Tryptophan a | + | + | 0.25–36 h |
15 | 5.34 | C7H6O3 | 139.0388 (−0.8) | 137.0249 (+3.6) | 121.0278 [M + H − H2O]+, 111.0072 [M + H − CO]+, 95.0482 [M + H − CO2]+, 77.0400 [M + H − H2O − CO2]+ | 93.0369 [M − H − CO2]−, 75.0272 [M − H − H2O − CO2]− | Hydroxybenzoic acid a | + | - | - |
16 | 6.04 | C9H11NO3 | 182.0810 (−0.6) | 180.0666 (+0) | 165.0550 [M + NH3]+ | - | Tyrosine a | + | + | 0.25–36 h |
17 | 8.17 | C16H18O9 | 355.1024 (+0.3) | 353.0878 (−0.11) | - | - | Chlorogenic acid a | + | - | - |
18 | 8.27 | C28H32O16 | 625.1763 (0) | 623.1624 (+1.1) | 463.1225 [M + H − glc]+, 301.0707 [M + H − 2glc]+, | 461.1109 [M − H − glc]−, 299.0574 [M − H − 2glc]− | Rhamnocitrin 3,4'-di-O-glucoside | + | - | 0.25-6 h |
19 | 8.97 | C9H8O4 | 181.0490 (−2.8) | 179.0357 (3.9) | 153.0544 [M + H − CO]+, 137.0314 [M + H − CO2]+, 123.0051, 93.0364 | 135.0467 [M − H − CO2]− | Caffeic acid a | + | - | 0.25−0.5 h |
20 | 9.49 | C9H10O5 | 199.0600 (−0.4) | 197.0455 (−0.14) | 181.0478 [M + H − H2O]+, 155.0694 [M + H − CO2]+, 125.0228 [M + H − CO2 − CH2O]+, 97.0298, 77.0388 | 182.0231 [M − H − CH3]−, 166.9992 [M − H − CH3O]−, 153.0572 [M − H − CO2]−, 123.0098 [M − H − CO2 − CH2O]−, 95.0153 | Syringic acid a | + | + | 0.25–36 h |
21 | 9.95 | C29H38O16 | - | 641.2085 (−0.28) | 665.2056 [M + Na] + (+0.7) | 479.1604 [M − H − glc]−, 317.1053 [M − H − 2glc]−, 195.0653 [M − H − 2glc − RDA]−, 121.0292 | Isomucronulatol-2',5'-di-O-glucoside | + | - | 0.25–3 h |
22 | 10.19 | C27H30O15 | 595.1652 (−0.8) | 593.1512 (−1.1) | 433.1137 [M + H − glc]+, 271.0596 [M + H − 2glc]+ | - | Emodin-di-O-glucoside | + | - | 0.25–4 h |
23 | 10.40 | C9H10O4 | 183.0654 (−0.8) | 181.0511 (+2.6) | 155.0696 [M + H − CO]+, 140.0466 [M + H − CO − CH3]+, 125.0220 [M + H − CO − CH2O]+, 123.0418 [M + H − 2CH2O]+, 95.0511, 77.0400 | - | Syringaldehyde a | + | - | 0.25–6 h |
24 | 10.73 | C17H24O9 | - | 371.1352 (+1.3) | 395.1314 [M + Na]+ (+0.4) | 209.0824 [M − H − glc]−, 193.0506, 178.0269 | Syringin a | + | + | 0.25–36 h |
25 | 11.20 | C10H10O4 | 195.0652 (+0.25) | 193.0510 (+1.9) | 177.0547 [M + H − H2O]+, 149.0590 [M + H − CH2O2]+, 163.0388 [M + H − CH3OH]+, 117.0333 [M + H − CH2O2 − CH3OH]+, 109.0271, 89.0380, 77.0387 | 178.0257 [M − H − CH3]−, 149.0611 [M − H − CO2]−, 134.0380 [M − H − CO2 − CH3]− | Ferulic acid a | + | + | 0.25–36 h |
26 | 11.31 | C22H22O11 | 463.1232 (−0.25) | 461.1099 (+2.1) | 301.0700 [M + H − glc]+, 269.0430 [M + H − glc − CH3OH]+, 241.0500, 213.0561, 197.0560 | 299.0568 [M − H − glc]−, 284.0336 [M − H − glc − CH3]+, 255.0308, 227.0334, 135.0092 | Pratensein-7-O-glucoside | + | - | 0.25–8 h |
27 | 11.90 | C10H10O4 | 195.0648 (−1.6) | 193.0509 (+1.6) | 177.0553 [M + H − H2O]+, 149.0631 [M + H − CH2O2]+, 117.0319 [M + H − CH2O2 − CH3OH]+, 89.0377 | 178.0259 [M − H − CH3]−, 149.069 [M − H − CO2]−, 134.0374 [M − H − CO2 − CH3]− | Isoferulic acid | + | + | 0.25–36 h |
28 | 12.03 | C11H12O5 | 225.0759 (+0.8) | 223.0617 (+2.3) | 247.0578 [M + Na]+, 207.0648 [M + H − H2O]+, 179.0671 [M + H − CH2O2]+, 175.0409 [M + H−H2O − CH3OH]+, 147.0418 [M + H − CH2O2 − CH3OH]+ | 205.0514 [M − H − H2O]−, 179.0710 [M − H − CO2]−, 163.0401 [M − H − 2CH2O]−, 161.0608 [M − H − H2O − CO2]−, 133.0661, 117.0720, 91.0569 | Sinapic acid | + | - | 0.25–3 h |
29 | 12.85 | C22H22O10 | 447.1290 (+1.1) | 445.1142 (+0.6) | 469.1106 [M + Na]+ (−0.3), 285.0767 [M + H − glc]+, 270.0523 [M + H − glc − CH3]+, 253.0501, 225.0553, 137.0238 | 283.0620 [M − H − glc]−, 268.0366 [M − H − glc − CH3]−, 233.0890, 203.0819, 159.0361 | Calycosin-7-O-glucoside a | + | - | 0.25–24 h |
30 | 13.25 | C21H20O10 | 433.1132 (+0.7) | 431.0985 (+0.25) | 271.0602 [M + H − glc]+, 215.0702 | 269.0390 [M − H − glc]−, 195.0509 | Cosmosiin a | + | + | 0.25–36 h |
31 | 15.08 | C29H38O15 | - | 625.2156 (+2.9) | 649.2115 [M + Na]+ (2.0), 487.1555 [M + Na − glc]+, 325.1390 [M + Na − 2glc]+, 177.0552 | 463.1635 [M − H − glc], 301.1097 [M − H − 2glc]−, 286.0850, 121.0300 | Isomucronulatol-7,2'-di-O-glucoside | + | - | 0.25–12 h |
32 | 15.27 | C9H16O4 | 189.1120 (−0.7) | 187.0985 (+4.7) | 211.0939 [M + Na]+ (+0.4), 165.1231 | 169.0875 [M − H − H2O]−, 143.1091 [M − H − CO2]−, 125.0980 [M − H − H2O − CO2]−, 97.0680, 95.0521 | Azelaic acid | + | + | 0.25–36 h |
33 | 15.75 | C22H22O9 | 431.1344 (+1.7) | 429.1193 (+0.6) | 453.1159 [M + Na]+ (+0.8), 269.0823 [M + H − glc]+, 254.0588, 213.0912 | 267.0681 [M − H − glc]− | Ononin a | + | - | 0.25–24 h |
34 | 15.94 | C23H26O10 | 463.1603 (+1.0) | 461.1449 (−0.9) | 301.1083 [M + H − glc]+, | 167.0706 | 9,10-dimethoxypterocarpan-3-O-glucoside | + | - | 0.25–12 h |
35 | 16.83 | C9H14O2 | 155.1065 (−1.1) | 153.0923 (+1.4) | 137.0969 [M + H − H2O]+, 109.1014 [M + H − CH2O2]+, 95.0859, 67.0569 | - | 2,4-Nonadienic acid | + | + | 0.25–36 h |
36 | 17.18 | C23 h28O10 | 465.1754 (−0.3) | 463.1611 (+0.21) | 487.1574 [M + Na]+ (+0), 303.1225 [M + H − glc]+, 167.0704, 123.0439 | 301.1092 [M − H − glc]−, 271.0629 [M − H − glc − CH3O]−, 165.0489, 121.0307, | Isomucronulatol-7-O-glucoside | + | - | 0.25–12 h |
37 | 17.42 | C16H12O5 | 285.0759 (+0.8) | 283.0622 (+3.8) | 270.0525 [M + H − CH3]+, 253.0490, 225.0534, 197.0596, 157.0641, 137.0223 | 239.0350, 211.0398, 195.0452, 167.0506, 148.0168, 135.0089 | Calycosin a | + | - | 0.25–24 h |
38 | 19.01 | C24H24O10 | 473.1442 (−0.1) | - | 455.3400 [M + H − H2O]+, 269.0795 [M + H−glc − C2H4O2]+ | - | 6'-O-acetyl ononin | + | - | 0.25–8 h |
39 | 20.09 | C16H12O4 | 269.0809 (+0.25) | 267.0669 (+2.4) | 253.0503, 237.0552, 225.0551, 213.0918, 197.0599, 181.0647 | 251.0358, 223.0401, 195.0453, 167.0505, 132.0223 | Formononetin a | + | - | 0.25–24 h |
40 | 22.25 | C47H78O19 | 947.5211 (+0.1) | 945.5112 (+5.0) | 969.5027 [M + Na]+ (−0.2) | 783.4625 [M − H − glc]−, 654.4278, 541.1990 | Astragaloside V | + | - | 0.25–24 h |
41 | 22.72 | C47H78O19 | 947.5223 (+1.3) | 945.5108 (+4.6) | 749.4493,617.4075, 587.3937, 969.5037 [M + Na]+ (+0.8), 473.3647,455.3527, 437.3421, 305.1585, 143.1067, 125.0987 | 783.4651 [M − H − glc]−, 489.3570, 161.0466 | Astragaloside VI | + | - | 0.25–24 h |
42 | 22.94 | C41H68O14 | 785.4676 (−0.7) | 783.4563 (3.5) | 807.4505 [M + Na]+ (+0.25) 605.4145, 455.3490, 437.1977, 419.3328 | 621.4056, 489.3691, 161.0458 | Astragaloside III | + | - | 0.25–12 h |
43 | 23.06 | C41H70O14 | - | 785.4704 (+1.5) | 809.4659 [M + Na]+ (+0.2) | 623.4223 [M − H − glc], 491.3752 [M − H − glc − xyl]−, 415.3217, 616.0448 | Cyclocanthoside E | + | - | 3 h |
44 | 24.03 | C47H78O19 | 947.5216 (+0.6) | 945.5116 (+5.5) | 965.5039 [M + Na]+ (+1.0) | 783.4630 [M − H − glc],765.4541, 651.4267, 489.3623, 179.0557, 161.0444 | Astragaloside VII | + | - | 0.25–12 h |
45 | 24.41 | C41H68O14 | 785.4682 (+0) | 783.4569 (+4.2) | 807.4089 [M + Na]+ (+0.9) | 621.4019, 489.3605, 383.2991, 161.0453 | Astragaloside IV a | + | - | 0.25–24 h |
46 | 24.63 | C43H70O15 | 827.4795 (+1.0) | 825.4669 (3.3) | 849.4615 [M + Na]+ (+1.0), 665.4299,647.4172, 473.3602, 455.3547, 437.3413, 175.0601 | - | Astragaloside II | + | - | 0.25−0.5 h, 6 h |
47 | 24.89 | C48H78O18 | 943.5254 (−0.7) | 941.5163 (+5.1) | 965.5072 [M + Na]+ (−0.8), 797.4635, 635.4105, 617.4020, 599.3916, 441.3704, 423.3577, 405.3532, 309.1134, 203.1766 | 923.5120, 733.4538, 615.4003, 457.3725, 247.0823, 205.7828 | Soyasaponin I | + | - | 0.25–24 h |
48 | 24.97 | C47H76O17 | - | 911.5032 (+2.5) | 935.4967 [M + Na]+ (−0.8), 477.115 | 703.4545, 615.3994, 571.4053, 457.3800, 247.0808, 205.0718 | Astragaloside VIII | + | - | 0.25–24 h |
49 | 25.71 | C45H72O16 | 869.4898 (+0.6) | 867.4785 (+4.4) | 831.4571, 711.4038, 651.3955, 591.3675, 447.3377 | 765.4573 | Astragaloside I | + | - | 0.25−0.5 h |
50 | 26.01 | C45H72O16 | 869.4887 (−0.6) | 867.4756 (+1.0) | 711.4037, 477.3364 | 807.4652, 765.4568, 179.0567 | Isoastragaloside I | + | - | 3 h |
51 | 27.35 | C47H74O17 | 911.4998 (+0) | 909.4888 (+3.8) | 875.4590, 753.4225, 731.4360, 477.3428, 437.3368, 259.0854, | 867.4787, 807.4666, 747.4616 | Acetyl astragaloside I | + | - | 8 h |
M1 | 14.34 | C16 H12O8S | 365.0323 (−0.5) | 363.0177 (−0.8) | 285.0782, 270.0522, 225.0537, 137.0254 | 283.0609, 268.0375, 211.0407, 148.0174 | Sulfated calycosin | - | - | 0.25–8 h |
M2 | 14.82 | C22H20O11 | 461.1081 (+0.7) | 459.0928 (−0.9) | 285.0766, 270.0534, 225.0541, 137.0230 | 283.0617, 268.0385, 239.0346, 211.0408, 175.0255, 117.0191, 113.0254, 85.0320 | Glucuronidated calycosin | - | - | 0.25–12 h |
M3 | 15.41 | C22H20O10 | 445.1133 (+1.0) | 443.0979 (−0.9) | 269.0817, 253.0486, 237.0516, 213.0904, 181.0650 | 267.0665, 252.0441, 175.0243, 113.0249 | Glucuronidated formononetin | - | - | 0.25–8 h |
M4 | 16.09 | C22H20O12 | 477.1027 (−0.1) | 475.0883 (+0.3) | 301.0761, 286.0475, 167.0661 | 299.0583, 284.0328, 255.0291, 227.0344, 175.0242, 151.0391, 113.0261 | Glucuronidated rhamnocitrin | - | - | 0.25–8 h |
M5 | 16.28 | C17H18O8S | 383.0798 (+0.9) | 381.0649 (+0.1) | - | 301.1082, 286.0827, 271.0624, 256.0363, 135.0450, 109.0312 | Sulfated isomucronulatol | - | - | 0.25–8 h |
M6 | 16.85 | C16H12O7S | 349.0378 (+0.6) | 347.0228 (−0.6) | 269.0792, 253.0507, 213.0941, 181.0629 | 267.0667, 252.0429, 223.0390 | Sulfated formononetin | - | - | 0.25–8 h |
M7 | 17.27 | C23H26O11 | 479.1544 (−0.7) | 477.1396 (−1.2) | 303.1219, 167.0707 | 301.1085, 286.0855, 271.0615, 256.0370, 175.0252, 135.0449, 113.0254 | Glucuronidated isomucronulatol | - | - | 0.25–12 h |
M8 | 18.45 | C16H12O6 | 301.0709 (+0.8) | 299.0561 (+0.3) | - | 284.0305, 255.0312, 227.0353, 183.0432, 135.0085 | Rhamnocitrin | - | - | 0.25–8 h |
M9 | 19.63 | C17H18O5 | 303.1229 (+0.7) | 301.1084 (+1.0) | 181.0841, 167.0688, 135.0339, 123.0440 | 286.0836, 271.0599, 256.0377, 135.0445, 121.0245, 109.0340 | Isomucronulatol | - | - | 0.25–8 h |
2.2. Characterization of the Absorbed Constituents in Mice Plasma
2.3. Identification of Metabolites in Mice Plasma
2.4. Pharmacokinetics of Calycosin-7-O-glucoside, Ononin, Calycosin, Formononetin and Astragaloside IV in Mice Plasma
2.4.1. Assay Validation
Compounds | Linear Range (ng/mL) | Linearity | r | LOD (ng/mL) | LOQ (ng/mL) | Intra-Day RSD (n = 6) | Inter-Day RSD (n = 3) | Accuracy | |
---|---|---|---|---|---|---|---|---|---|
Mean (%) | RSD (%) | ||||||||
Calycosin-7-O-glucoside | 4.48–448.00 | y = 0.7300x − 0.0017 | 0.9982 | 0.64 | 2.28 | 1.28 | 3.20 | 95.21 | 1.63 |
Ononin | 3.40–340.00 | y = 0.2847x + 0.0009 | 0.9994 | 0.52 | 1.70 | 2.16 | 3.11 | 97.03 | 2.18 |
Calycosin | 4.47–447.00 | y = 0.7951x − 0.0047 | 0.9987 | 0.84 | 2.24 | 1.22 | 2.95 | 104.58 | 2.56 |
Formononetin | 5.52–552.00 | y = 0.3547x + 0.0021 | 0.9949 | 0.68 | 2.76 | 2.77 | 3.64 | 102.21 | 1.40 |
Astragaloside IV | 8.98–898.00 | y = 0.8558x + 0.0031 | 0.9923 | 1.28 | 4.49 | 3.84 | 4.37 | 98.48 | 2.87 |
2.4.2. Pharmacokinetics Study
Compounds | Parameter | ||||
---|---|---|---|---|---|
AUC(0–t) (ng/mL∙h) | AUC(0–∞) (ng/mL∙h) | t1/2z (h) | tmax (h) | Cmax (ng/mL) | |
Calycosin-7-O-glucoside | 108.16 ± 37.14 | 127.17 ± 40.31 | 2.61 ± 0.67 | 1.5 | 33.41 |
Ononin | 227.84 ± 59.69 | 239.24 ± 47.38 | 1.96 ± 0.34 | 1.5 | 51.38 |
Calycosin | 135.88 ± 41.41 | 154.87 ± 37.69 | 2.21 ± 0.92 | 1.5 | 32.98 |
Formononetin | 233.38 ± 47.83 | 256.42 ± 45.68 | 3.99 ± 1.03 | 2.0 | 47.93 |
Astragaloside IV | 695.37 ± 178.57 | 722.49 ± 196.52 | 3.48 ± 1.15 | 1.5 | 128.95 |
2.5. Discussion
3. Experimental Section
3.1. Chemicals and Reagents
3.2. Plant Material and Sample Preparation
3.3. Animals and Experiment Design
3.4. Preparation of Plasma Samples
3.5. Bioanalytical Methods
4. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Liu, M.; Li, P.; Zeng, X.; Wu, H.; Su, W.; He, J. Identification and Pharmacokinetics of Multiple Potential Bioactive Constituents after Oral Administration of Radix Astragali on Cyclophosphamide-Induced Immunosuppression in Balb/c Mice. Int. J. Mol. Sci. 2015, 16, 5047-5071. https://doi.org/10.3390/ijms16035047
Liu M, Li P, Zeng X, Wu H, Su W, He J. Identification and Pharmacokinetics of Multiple Potential Bioactive Constituents after Oral Administration of Radix Astragali on Cyclophosphamide-Induced Immunosuppression in Balb/c Mice. International Journal of Molecular Sciences. 2015; 16(3):5047-5071. https://doi.org/10.3390/ijms16035047
Chicago/Turabian StyleLiu, Menghua, Panlin Li, Xuan Zeng, Huanxian Wu, Weiwei Su, and Jingyu He. 2015. "Identification and Pharmacokinetics of Multiple Potential Bioactive Constituents after Oral Administration of Radix Astragali on Cyclophosphamide-Induced Immunosuppression in Balb/c Mice" International Journal of Molecular Sciences 16, no. 3: 5047-5071. https://doi.org/10.3390/ijms16035047