Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2497108 | Phytomedicine | 2010 | 9 Pages |
The effects of Danshen and its active components (tanshinone I, tanshinone IIA, dihydrotanshinone and cryptotanshinone) on tolbutamide 4-hydroxylation was investigated in the rat. Danshen (0.125–2 mg/ml) decreased 4-hydroxy-tolbutamide formation in vitro and in vivo. Enzyme kinetics studies showed that inhibition of tolbutamide 4-hydroxylase activity was competitive and concentration-dependent. The Ki values of the tanshinones were: dihydrotanshinone (8.92 μM), cryptotanshinone (24.5 μM), tanshinone I (80.3 μM) and tanshinone IIA (242.9 μM). In freshly prepared primary rat hepatocytes, tanshinones inhibited tolbutamide 4-hydroxylation in a concentration-dependent manner, with EC40 values in the order: cryptotanshinone (15.8 μM), tanshinone IIA (16.2 μM), dihydrotanshinone (20.1 μM) and tanshinone I (48.2 μM). In whole animal studies, single dose Danshen treatment (50 or 200 mg/kg, i.p.) increased tolbutamide clearance (17–26.9%), decreased AUC (14.4–20.9%) and increased the Vd (7.26%). Three-day Danshen treatment (200 mg/kg/day, i.p.) decreased the Cinitial, increased T1/2 and Vd but did not affect tolbutamide clearance and AUC. Tolbutamide-4-hydroxylation in vivo was decreased by Danshen after acute and after 3-day treatment, with decreases in the AUC of 4-hydroxy-tolbutamide (15–28%) over the time period studied. Despite competitive inhibition of rat CYP2C11 in vitro and in vivo, as shown by the decrease in tolbutamide 4-hydroxylation, only minor changes in tolbutamide pharmacokinetics was observed. This study illustrated that the herb-drug interaction potential should be monitored by both in vitro and in vivo biotransformation/ pharmacokinetic parameters.