title: The effects of milk thistle (Silybum marianum) on human cytochrome P450 activity.
abstract: Milk thistle (Silybum marianum) extracts are widely used as a complementary and alternative treatment of various hepatic conditions and a host of other diseases/disorders. The active constituents of milk thistle supplements are believed to be the flavonolignans contained within the extracts. In vitro studies have suggested that some milk thistle components may significantly inhibit specific cytochrome P450 (P450) enzymes. However, determining the potential for clinically significant drug interactions with milk thistle products has been complicated by inconsistencies between in vitro and in vivo study results. The aim of the present study was to determine the effect of a standardized milk thistle supplement on major P450 drug-metabolizing enzymes after a 14-day exposure period. CYP1A2, CYP2C9, CYP2D6, and CYP3A4/5 activities were measured by simultaneously administering the four probe drugs, caffeine, tolbutamide, dextromethorphan, and midazolam, to nine healthy volunteers before and after exposure to a standardized milk thistle extract given thrice daily for 14 days. The three most abundant falvonolignans found in plasma, following exposure to milk thistle extracts, were silybin A, silybin B, and isosilybin B. The concentrations of these three major constituents were individually measured in study subjects as potential perpetrators. The peak concentrations and areas under the time-concentration curves of the four probe drugs were determined with the milk thistle administration. Exposure to milk thistle extract produced no significant influence on CYP1A2, CYP2C9, CYP2D6, or CYP3A4/5 activities.
authors.affiliation: Department of Pharmacotherapy and Translational Research (M.K.-S., R.F.F., B.J.B., J.S.M.) and Center for Pharmacogenomics (M.K.-S., R.F.F., J.S.M.), University of Florida, Gainesville, Florida; Department of Clinical, Social, and Administrative Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan (H.-J.Z.); and Department of Surgery, Division of Transplantation (K.D.C.), and Department of Psychiatry and Behavioral Sciences (H.J.B.), Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Marina
authors.initials: M
authors.lastname: Kawaguchi-Suzuki
authors.affiliation: Department of Pharmacotherapy and Translational Research (M.K.-S., R.F.F., B.J.B., J.S.M.) and Center for Pharmacogenomics (M.K.-S., R.F.F., J.S.M.), University of Florida, Gainesville, Florida; Department of Clinical, Social, and Administrative Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan (H.-J.Z.); and Department of Surgery, Division of Transplantation (K.D.C.), and Department of Psychiatry and Behavioral Sciences (H.J.B.), Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Reginald F
authors.initials: RF
authors.lastname: Frye
authors.affiliation: Department of Pharmacotherapy and Translational Research (M.K.-S., R.F.F., B.J.B., J.S.M.) and Center for Pharmacogenomics (M.K.-S., R.F.F., J.S.M.), University of Florida, Gainesville, Florida; Department of Clinical, Social, and Administrative Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan (H.-J.Z.); and Department of Surgery, Division of Transplantation (K.D.C.), and Department of Psychiatry and Behavioral Sciences (H.J.B.), Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Hao-Jie
authors.initials: HJ
authors.lastname: Zhu
authors.affiliation: Department of Pharmacotherapy and Translational Research (M.K.-S., R.F.F., B.J.B., J.S.M.) and Center for Pharmacogenomics (M.K.-S., R.F.F., J.S.M.), University of Florida, Gainesville, Florida; Department of Clinical, Social, and Administrative Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan (H.-J.Z.); and Department of Surgery, Division of Transplantation (K.D.C.), and Department of Psychiatry and Behavioral Sciences (H.J.B.), Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Brinda
authors.affiliation: Department of Pharmacotherapy and Translational Research (M.K.-S., R.F.F., B.J.B., J.S.M.) and Center for Pharmacogenomics (M.K.-S., R.F.F., J.S.M.), University of Florida, Gainesville, Florida; Department of Clinical, Social, and Administrative Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan (H.-J.Z.); and Department of Surgery, Division of Transplantation (K.D.C.), and Department of Psychiatry and Behavioral Sciences (H.J.B.), Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Chavin
authors.affiliation: Department of Pharmacotherapy and Translational Research (M.K.-S., R.F.F., B.J.B., J.S.M.) and Center for Pharmacogenomics (M.K.-S., R.F.F., J.S.M.), University of Florida, Gainesville, Florida; Department of Clinical, Social, and Administrative Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan (H.-J.Z.); and Department of Surgery, Division of Transplantation (K.D.C.), and Department of Psychiatry and Behavioral Sciences (H.J.B.), Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Hilary J
authors.initials: HJ
authors.lastname: Bernstein
authors.affiliation: Department of Pharmacotherapy and Translational Research (M.K.-S., R.F.F., B.J.B., J.S.M.) and Center for Pharmacogenomics (M.K.-S., R.F.F., J.S.M.), University of Florida, Gainesville, Florida; Department of Clinical, Social, and Administrative Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan (H.-J.Z.); and Department of Surgery, Division of Transplantation (K.D.C.), and Department of Psychiatry and Behavioral Sciences (H.J.B.), Medical University of South Carolina, Charleston, South Carolina jmarkowitz@cop.ufl.edu.
authors.forename: John S
authors.initials: JS
authors.lastname: Markowitz
mesh_terms: D002110:Caffeine / Q000493:pharmacokinetics; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003915:Dextromethorphan / Q000493:pharmacokinetics; D019587:Dietary Supplements / Q000032:analysis; D005260:Female; D041743:Herb-Drug Interactions; D006801:Humans; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics; D020944:Silybum marianum / Q000737:chemistry*; D010936:Plant Extracts / Q000494:pharmacology*; D000077385:Silybin; D012838:Silymarin / Q000031:analogs & derivatives / Q000097:blood; D014044:Tolbutamide / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D010936:Plant Extracts; D012838:Silymarin; D002110:Caffeine; D000077385:Silybin; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D014044:Tolbutamide; C523198:isosilybin A; D008874:Midazolam