Pharmacokinetic interaction studies of tanshinones with tolbutamide, a model CYP2C11 probe substrate, using liver microsomes, primary hepatocytes and in vivo in the rat
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AbstractThe 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 K(i) values of the tanshinones were: dihydrotanshinone (8.92 mu M), cryptotanshinone (24.5 mu M), tanshinone I (80.3 mu M) and tanshinone IIA (242.9 mu M). In freshly prepared primary rat hepatocytes, tanshinones inhibited tolbutamide 4-hydroxylation in a concentration-dependent manner, with EC(40) values in the order: cryptotanshinone (15.8 mu M), tanshinone IIA (16.2 mu M), dihydrotanshinone (20.1 mu M) and tanshinone I (48.2 mu M). 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 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. (C) 2009 Elsevier GmbH. All rights reserved.
All Author(s) ListWang X, Lee WYW, Or PMY, Yeung JHK
Journal namePhytomedicine
Year2010
Month3
Day1
Volume Number17
Issue Number3-4
PublisherELSEVIER GMBH, URBAN & FISCHER VERLAG
Pages203 - 211
ISSN0944-7113
eISSN1618-095X
LanguagesEnglish-United Kingdom
Keywords4-Hydroxy tolbutamide; Danshen (Salvia miltiorrhiza); Rat CYP2C11 activity; Tanshinones; Tolbutamide metabolism
Web of Science Subject CategoriesChemistry, Medicinal; CHEMISTRY, MEDICINAL; Integrative & Complementary Medicine; INTEGRATIVE & COMPLEMENTARY MEDICINE; Pharmacology & Pharmacy; PHARMACOLOGY & PHARMACY; Plant Sciences; PLANT SCIENCES

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