Relationships between the Toxicities of Radix Aconiti Lateralis Preparata (Fuzi) and the Toxicokinetics of Its Main Diester-Diterpenoid Alkaloids
Abstract
:1. Introduction
2. Classification of Aconitum Alkaloids
3. Toxicities of the Main Diester-Diterpenoid Alkaloids in Fuzi
3.1. Clinical Toxicities of Fuzi
3.2. Toxicities of Fuzi and Its Main Diester-Diterpenoid Alkaloids in Pre-Clinical Models
4. Toxicokinetic Characteristics of the Main Diester-Diterpenoid Alkaloids in Fuzi
4.1. Toxicokinetic Profiles of the Main Diester-Diterpenoid Alkaloids in Humans after Ingestion of Fuzi
4.2. Toxicokinetic Characteristics of the Main Diester-Diterpenoid Alkaloids of Fuzi in Pre-Clinical Models
4.2.1. Absorption
4.2.2. Distribution
4.2.3. Metabolism
4.2.4. Excretion
4.2.5. Modulation of the Transporters and Enzymes
5. Relationships between Toxicities of Fuzi Extract and the Toxicokinetic Profiles of Its Main Diester-Diterpenoid Alkaloids
5.1. Relationship between the Cardiac Toxicity and the Toxicokinetic Profiles of the Main Diester-Diterpenoid Alkaloids after Oral Intake of Their Pure Compounds
5.1.1. Relationship between the Acute Cardiac Toxicity and Toxicokinetic Profiles of the Main Diester-Diterpenoid Alkaloids after a Single Oral Dose
5.1.2. Relationship between the Sub-Chronic Toxicity and Toxicokinetic Profiles of the Aconitine after Multiple Oral Doses
5.2. Relationship between the Heart, Liver, and Kidney Toxicities of Fuzi and the Toxicokinetics of Its Main Diester-Diterpenoid Alkaloids after Oral Intake of Its Extract
5.2.1. Dose-Dependent Toxicities of Fuzi and the Toxicokinetic Profiles of Its Main Diester-Diterpenoid Alkaloids after Single Oral Administration
AC-Related Toxicokinetic Profiles at the Toxic Level of Fuzi
HA-Related Toxicokinetic Profiles at the Toxic Level of Fuzi
MA-Related Toxicokinetic Profiles at the Toxic Level of Fuzi
5.2.2. Dose-Dependent Toxicity of Fuzi and the Toxicokinetic Profile of Its Main Diester-Diterpenoid Alkaloids after Long-Term Oral Administration
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Compound | Species | Duration/Dose | Toxicokinetic Parameters | Pharmacokinetics in Heart | Toxicity Measurement | Reference | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Tmax (min) | Cmax (ng/mL) | T1/2 (min) | AUC0-last (min·ng/mL) | Tmax (min) | Cmax (ng/g) | Serum Biomarker | Heart Histology | ECG | Behavior | ||||
AC | Mice | 7 days/0.146 mg/kg | NR | NR | NR | NR | NR | NR | ↑ CK, AST, LDH | Hyper-chromatic nuclei, condensed cytoplasm | Ventricular tachycardia | NR | [25] |
22 days/1 mg/kg | NR | ↓compared to single dose | NR | NR | NR | ↓compared to single dose | NR | NR | NR | ↓ Body weight ↓ Rectal temperature | [65] | ||
Single dose/0.1 mg/kg | 23.3 ± 2.1 | 6.5 ± 0.5 | 58.8 ± 5.5 | 671.4 ± 63.0 | 10 | 10.6 ± 2.7 | NS vs. control on CK, s-100 β | NS vs. control | NR | NS vs. control | [49] | ||
Single dose/0.2 mg/kg | 35.0 ± 6.0 | 13.0 ± 0.9 | 69.1 ± 8.2 | 1578.4 ± 118.8 | 30 | 14.9 ± 2.6 | NR | NR | NR | Inactive, abnormal pulsation and breathing | [49] | ||
Single dose/1 mg/kg | 15 | 8.5 ± 0.4 | NR | NR | 14.85 | 71.3 ± 5.5 | NR | NR | Arrhythmias | 14% Dead | [21] | ||
Rats | 7 days/0.504 mg/kg | 25.0 ± 4.4 | 10.1 ± 2.1 | 211.8 ± 20.0 | 3329.4 ± 1199.0 | NR | NR | NR | NR | NR | NR | [44] | |
Single dose/0.1 mg/kg | 37.5 ± 3.0 | 6.9 ± 0.8 | NR | 1485.7 ± 144.3 | NR | NR | NR | NR | NS vs. control on heart rate | NR | [17] | ||
Single dose/0.2 mg/kg | 52.2 ± 13.2 | 39.4 ± 3.2 | 100.2 ± 12.6 | 9043.8 ± 725.4 | NR | NR | NR | NR | NR | NR | [46] | ||
Single dose/0.2 mg/kg | 46.0 ± 15.0 | 9.7 ± 1.9 | 77.2 ± 8.4 | 1650.3 ± 359.2 | NR | NR | NR | NR | NR | NR | [66] | ||
Single dose/0.2 mg/kg | 25.5 ± 5.8 | 7.5 ± 0.8 | NR | 1582.9 ± 125.1 | NR | NR | NR | NR | ↓ Heart rate | NR | [17] | ||
Single dose/0.4 mg/kg | 130.7 ± 10.0 | 7.7 ± 0.9 | NR | 2884.7 ± 135.9 | NR | NR | NR | NR | ↓ Heart rate | ↓ Blood pressure | [17] | ||
Single dose/0.5 mg/kg | 30.1 ± 9.7 | 8.7 ± 5.3 | 223.2 ± 53.0 | 2913.5 ± 981.1 | NR | NR | NR | NR | NR | NR | [44] | ||
Single dose/0.5 mg/kg | 47.0 ± 8.4 | 44.3 ± 13.0 | 56.1 ± 15.6 | 10,092.0 ± 964.8 | NR | NR | NR | NR | NR | NR | [67] | ||
HA | Rats | Single dose/2 mg/kg | 240 | 2.73 | 145.38 | 834.03 | 15 | 4.6 ± 5.9 | NR | NR | NR | 5% dead | [63] |
Dog | Single dose/0.05 mg/kg | 60 | 1.53 | NR | NR | NR | NR | NR | NR | Prolonged QT interval | NR | [40] | |
Single dose/0.15 mg/kg | 60 | 5.74 | NR | NR | NR | NR | NR | NR | Prolonged QT interval | NR | [40] | ||
Single dose/0.45 mg/kg | 60 | 10.11 | NR | NR | NR | NR | NR | NR | Prolonged QT interval | NR | [40] |
Species | Extract Dose | Dose of Components (mg/kg) | Targeted Compound | Toxicokinetic Parameters | Toxicity Measurements | Reference | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
DDAs | AC | HA | MA | Tmax (min) | Cmax (ng/mL) | T1/2 (min) | AUC0-last (min·ng/mL) | Serum | Heart | Liver | Kidney | ||||
Beagle dog | Fuzi extract 1.5 g/kg | 0.940 | 0.121 | 0.406 | 0.413 | AC | 70 ± 9 | 14.1 ± 0.8 | 273 ± 5 | 5514 ± 76 | NR | NR | NR | NR | [74] |
HA | 70 ± 9 | 43.2 ± 1.5 | 292 ± 14 | 18,891 ± 455 | NR | NR | NR | NR | |||||||
MA | 70 ± 9 | 45.4 ± 1.8 | 375 ± 6 | 21,638 ± 144 | NR | NR | NR | NR | |||||||
Rats | Fuzi extract 0.2 g/kg | 0.356 | 0.037 | 0.181 | 0.138 | AC | 120 ± 60 | 1.0 ± 0.1 | 84 ± 16 | 257 ± 45 | NR | NR | NR | NR | [68] |
HA | 160 ± 92 | 5.3 ± 0.2 | 104 ± 2 | 1485 ± 243 | NR | NR | NR | NR | |||||||
MA | 132 ± 96 | 1.9 ± 0.3 | 89 ± 5 | 477 ± 175 | NR | NR | NR | NR | |||||||
Chuanwu extract NR | 0.46 | 0.06 | 0.10 | 0.30 | AC | 105 ± 16 | 1.3 ± 0.5 | 294 ± 312 | 353 ± 113 | NR | NR | NR | NR | [69] | |
HA | 105 ± 18 | 3.0 ± 0.6 | 180 ± 81 | 786 ± 180 | NR | NR | NR | NR | |||||||
MA | 105 ± 18 | 3.3 ± 1.0 | 251 ± 198 | 840 ± 204 | NR | NR | NR | NR | |||||||
0.66 | 0.06 | 0.30 | 0.30 | AC | 20 ± 8 | 2.1 ± 1.3 | 462 ± 292 | 498 ± 84 | NR | NR | NR | NR | |||
HA | 20 ± 11 | 7.5 ± 3.2 | 310 ± 102 | 2184 ± 708 | NR | NR | NR | NR | |||||||
MA | 25 ± 12 | 6.1 ± 3.8 | 636 ± 210 | 1200 ± 252 | NR | NR | NR | NR | |||||||
Fuzi extract 5.4 g/kg | 2.951 | 0.078 | 2.856 | 0.017 | AC | 41 ± 14 | 0.9 ± 0.1 | 220 ± 27 | 340 ± 40 | NR | NR | NR | NR | [70] | |
HA | 71 ± 14 | 31.7 ± 1.6 | 253 ± 67 | 13,910 ± 2504 | NR | NR | NR | NR | |||||||
MA | 56 ± 8 | 1.0 ± 0.1 | 192 ± 49 | 380 ± 31 | NR | NR | NR | NR | |||||||
Fuzi extract 0.0384 g/kg | 4.900 | 0.177 | 2.918 | 1.805 | AC | 60 ± 0 | 10.2 ± 1.5 | 644 ± 29 | 4297 ± 1570 | NR | NR | NR | NR | [71] | |
HA | 60 ± 0 | 60.2 ± 4.3 | 559 ± 62 | 24,635 ± 100 | NR | NR | NR | NR | |||||||
MA | 60 ± 0 | 24.8 ± 4.2 | 617 ± 23 | 10,988 ± 2192 | NR | NR | NR | NR | |||||||
Fuzi extract 4.5 g/kg | NR | 0.118 | NR | NR | AC | 58 ± 22 | 3.2 ± 0.4 | 218 ± 86 | 640 ± 107 | NR | NR | NR | NR | [44] | |
Fuzi extract 2 g/kg | 1.169 | 0.116 | 0.586 | 0.467 | NA | NR | NR | NR | NR | NS vs. control on CK, LDH, ALT, AST, and Urea | Nuclear varies in size | Mild edema | NS vs. control | [26] | |
Fuzi extract 5 g/kg | 2.924 | 0.290 | 1.466 | 1.168 | NA | NR | NR | NR | NR | ↑ LDH | Dilated blood vessels | Mild edema | Scattered lymphocytes | ||
Fuzi extract 10 g/kg | 5.848 | 0.580 | 2.932 | 2.336 | NA | NR | NR | NR | NR | ↑ CK, LDH, AST, Urea | Nuclear varies in size | Edema | Scattered atrophy |
Duration | Extract Dosage | Dose of Components (mg/kg) | Targeted Compound | Toxicokinetic Parameters | Toxicity Measurements | Reference | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
DDAs | AC | HA | MA | Tmax (min) | Cmax (ng/mL) | T1/2 (min) | AUC0-last (min·ng/mL) | Serum | Heart | Liver | Kidney | ||||
7 days | Fuzi 4.5 g/kg | 0.118 | 0.118 | NR | NR | AC | 20 ± 9 | 2.6 ± 1.0 | 384 ± 97 | 989 ± 67 | NR | NR | NR | NR | [44] |
Fuzi 17.6 g/kg | 2.066 | 0.000 | 0.804 | 1.262 | NA | NR | NR | NR | NR | NS vs. control on BUN | NR | NR | NR | [72] | |
Fuzi 35.6 g/kg | 4.180 | 0.000 | 1.627 | 2.553 | NA | NR | NR | NR | NR | NS vs. control on BUN | NR | NR | NR | ||
Fuzi 88.1 g/kg | 10.343 | 0.000 | 4.026 | 6.317 | NA | NR | NR | NR | NR | ↓ BUN | NR | NR | NR | ||
15 days | Baifupian 0.32 g/kg | 0.175 | 0.005 | 0.162 | 0.008 | NA | NR | NR | NR | NR | NS vs. control on Creatine, BUN, ALT, CK, and LDH | NR | NR | NR | [23] |
Baifupian 0.64 g/kg | 0.055 | 0.010 | 0.324 | 0.016 | NA | NR | NR | NR | NR | NS vs. control on Creatine, BUN, ALT, CK and LDH | NR | NR | NR | ||
Baifupian 1.28 g/kg | 0.11 | 0.02 | 0.647 | 0.032 | NA | NR | NR | NR | NR | ↑ Creatine, BUN, ALT, CK, and LDH | NR | NR | NR | ||
Baifupian 2.56 g/kg | 0.22 | 0.04 | 1.294 | 0.064 | NA | NR | NR | NR | NR | ↑ Creatine, BUN, ALT, CK, and LDH | Inflammatory infiltration edema | Necrosis inflammation | Vascular dilatation |
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Yang, M.; Ji, X.; Zuo, Z. Relationships between the Toxicities of Radix Aconiti Lateralis Preparata (Fuzi) and the Toxicokinetics of Its Main Diester-Diterpenoid Alkaloids. Toxins 2018, 10, 391. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins10100391
Yang M, Ji X, Zuo Z. Relationships between the Toxicities of Radix Aconiti Lateralis Preparata (Fuzi) and the Toxicokinetics of Its Main Diester-Diterpenoid Alkaloids. Toxins. 2018; 10(10):391. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins10100391
Chicago/Turabian StyleYang, Mengbi, Xiaoyu Ji, and Zhong Zuo. 2018. "Relationships between the Toxicities of Radix Aconiti Lateralis Preparata (Fuzi) and the Toxicokinetics of Its Main Diester-Diterpenoid Alkaloids" Toxins 10, no. 10: 391. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins10100391