Preclinical evaluation of milk thistle– and resveratrol–drug interaction liability in rodents
| Preparation and Administration Regimen | Rodent | Test Substrate Administration Regimen | Enzymea or Transporter | Metric/Outcome | Reference |
|---|---|---|---|---|---|
| Silibinin 0.5 mg/kg p.o. | Rats (6/arm) | Tamoxifen 10 mg/kg p.o | Cyp3a Cyp2d P-gp | 1.2-fold ↑ in Cmax 1.2-fold ↑ in AUC | Kim et al. (2010) |
| Silibinin 2.5 mg/kg p.o. | 1.5-fold ↑ in Cmax 1.4-fold ↑ in AUC | ||||
| Silibinin 10 mg/kg p.o. | 1.8-fold ↑ in Cmax 1.7-fold ↑ in AUC | ||||
| Silibinin 175 mg/kg p.o. 7 d prior to test substrate | Male Sprague-Dawley Rats (6 per arm) | Trazodone 5 mg/kg i.v.c | Cyp3a | 12% ↓ in Cmax | Chang et al. (2009) |
| No change in AUC | |||||
| Silibinin 350 mg/kg p.o. 7 d prior to test substrate | 30% ↓ in Cmax 8% ↓ in AUC | ||||
| Silymarin 500 mg/kg p.o. 7 d prior to test substrate | No change in Cmax | ||||
| 20% ↓ in AUC | |||||
| Silymarin 1000 mg/kg p.o. 7 d prior to test substrate | No change in Cmax | ||||
| 43% ↓ in AUC | |||||
| Silymarin 1000 mg/kg p.o. 4 h prior to test substrate | 238% ↑ in Cmax 3% ↑ in AUC | ||||
| Silymarin 40 mg/kg p.o. coadministered with test substrate | Male Sprague-Dawley Rats (5 per arm) | Risperidone 6 mg/kg p.o. | P-gp | 1.3-fold ↑ in Cmax | Lee et al. (2013) |
| No change in AUC | |||||
| Silymarin 40 mg/kg p.o. 5 d prior to test substrate | 2.4-fold ↑ in Cmax 1.7-fold ↑ in AUC | ||||
| Silibinin 30 mg/kg i.v. | Rats (6 per arm) | Pyrazinamide 50 mg/kg i.v. | Xanthine oxidase | 21% ↑ in Cmax | Wu and Tsai (2007) |
| 5% ↑ in AUC | |||||
| Pyrazinoic acid 30 mg/kg i.v. | 320% ↑ in Cmax | ||||
| 420% ↑ in AUC | |||||
| Silibinin 100 mg/kg p.o for 4 d | Pyrazinamide 50 mg/kg i.v. | 22% ↑ in Cmax | |||
| 6% ↓ in AUC | |||||
| Pyrazinoic acid 30 mg/kg i.v. | 260% ↑ in Cmax | ||||
| 350% ↑ in AUC | |||||
| Resveratrol 0.3 or 1 g/kg per day p.o. for 28 d | Male and female CD rats (5 per arm) | NA | Cyp, Ugt, Gst, Nqo-1 | ↑ in Gst, Nqo-1, and Ugt1a1, Ugt1a6, and Ugt1a7 mRNA in liver | Hebbar et al. (2005) |
| Resveratrol 0.5–10 mg/kg intragastric | Male Sprague-Dawley rats (6 per arm) | Diltiazem 5 mg/kg i.v. or 15 mg/kg p.o. | Cyp3a, P-gp | 20%–60% ↑ in bioavailability | Hong et al. (2008) |
| Resveratrol 10 mg/kg i.p. | Male Swiss albino mice (3 to 4 per arm) | Pyrogallol 40 mg/kg i.p. for 1–4 wk | Cyp, Gst | ↓ in Cyp1a2 and Cyp2e1 activity, ↑ in Gst activity | Upadhyay et al. (2008) |
| Resveratrol 25–50 mg/kg i.p. once daily for 1 or 7 d | Male Swiss albino CD1 mice (8 per arm) | NA | Cyp, Ugt, Gst | Up to 67% ↓ in hepatic and up to 97% ↓ in lung Cyp activity | Canistro et al. (2009) |
| 83% ↑ in hepatic Ugt activity | |||||
| 83% ↓ in lung Ugt activity | |||||
| 22% ↓ in hepatic Gst activity | |||||
| 76% ↓ in lung Gst activity |
NA, not applicable.
↵a Human ortholog responsible for metabolism or transport of test substrate.