title: Modulation of esterified drug metabolism by tanshinones from Salvia miltiorrhiza ("Danshen").
abstract: The roots of Salvia miltiorrhiza ("Danshen") are used in traditional Chinese medicine for the treatment of numerous ailments including cardiovascular disease, hypertension, and ischemic stroke. Extracts of S. miltiorrhiza roots in the formulation "Compound Danshen Dripping Pill" are undergoing clinical trials in the United States. To date, the active components of this material have not been conclusively identified. We have determined that S. miltiorrhiza roots contain potent human carboxylesterase (CE) inhibitors, due to the presence of tanshinones. K(i) values in the nM range were determined for inhibition of both the liver and intestinal CEs. As CEs hydrolyze clinically used drugs, the ability of tanshinones and S. miltiorrhiza root extracts to modulate the metabolism of the anticancer prodrug irinotecan (CPT-11) was assessed. Our results indicate that marked inhibition of human CEs occurs following incubation with both pure compounds and crude material and that drug hydrolysis is significantly reduced. Consequently, a reduction in the cytotoxicity of irinotecan is observed following dosing with either purified tanshinones or S. miltiorrhiza root extracts. It is concluded that remedies containing tanshinones should be avoided when individuals are taking esterified agents and that patients should be warned of the potential drug-drug interaction that may occur with this material.
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: M Jason
authors.initials: MJ
authors.lastname: Hatfield
authors.forename: Lyudmila G
authors.initials: LG
authors.lastname: Tsurkan
authors.forename: Janice L
authors.initials: JL
authors.lastname: Hyatt
authors.forename: Carol C
authors.initials: CC
authors.lastname: Edwards
authors.forename: Andrew
authors.initials: A
authors.lastname: Lemoff
authors.forename: Cynthia
authors.initials: C
authors.lastname: Jeffries
authors.forename: Bing
authors.initials: B
authors.lastname: Yan
authors.forename: Philip M
authors.initials: PM
authors.lastname: Potter
mesh_terms: D045784:Abietanes / Q000737:chemistry / Q000302:isolation & purification* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000465:Algorithms; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D043182:Carboxylesterase / Q000037:antagonists & inhibitors*; D017321:Clinical Trials, Phase I as Topic; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D041743:Herb-Drug Interactions; D006801:Humans; D000077146:Irinotecan; D008516:Medicine, Chinese Traditional; D015394:Molecular Structure; D010618:Phenanthrolines / Q000494:pharmacology*; D018517:Plant Roots / Q000737:chemistry; D027561:Salvia miltiorrhiza / Q000737:chemistry*
chemical_list: D045784:Abietanes; D004365:Drugs, Chinese Herbal; D010618:Phenanthrolines; C021751:tanshinone; C028972:dan-shen root extract; D000077146:Irinotecan; D043182:Carboxylesterase; D002166:Camptothecin