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 (0.125-2mg/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 K(i) values of the tanshinones were: dihydrotanshinone (8.92microM), cryptotanshinone (24.5microM), tanshinone I (80.3microM) and tanshinone IIA (242.9microM). In freshly prepared primary rat hepatocytes, tanshinones inhibited tolbutamide 4-hydroxylation in a concentration-dependent manner, with EC(40) values in the order: cryptotanshinone (15.8microM), tanshinone IIA (16.2microM), dihydrotanshinone (20.1microM) and tanshinone I (48.2microM). In whole animal studies, single dose Danshen treatment (50 or 200mg/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 (200mg/kg/day, i.p.) decreased the C(initial), increased T(1/2) 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.
Copyright 2009 Elsevier GmbH. All rights reserved.