title: Pharmacokinetic interaction studies of tanshinones with tolbutamide, a model CYP2C11 probe substrate, using liver microsomes, primary hepatocytes and in vivo in the rat.
abstract: 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.
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: W Y W
authors.initials: WY
authors.lastname: Lee
authors.forename: P M Y
authors.initials: PM
authors.lastname: Or
authors.forename: J H K
authors.initials: JH
authors.lastname: Yeung
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D002478:Cells, Cultured; D000072467:Cytochrome P450 Family 2; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000378:metabolism; D041743:Herb-Drug Interactions; D006900:Hydroxylation / Q000187:drug effects; D008658:Inactivation, Metabolic; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D023421:Models, Animal; D010616:Phenanthrenes / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D027561:Salvia miltiorrhiza / Q000737:chemistry*; D039181:Steroid 16-alpha-Hydroxylase / Q000378:metabolism*; D014044:Tolbutamide / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D010616:Phenanthrenes; D010936:Plant Extracts; D014044:Tolbutamide; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase