RT Journal Article SR Electronic T1 Hepatic Metabolism and Biliary Excretion of Silymarin Flavonolignans in Isolated Perfused Rat Livers: Role of Multidrug Resistance-Associated Protein 2 (Abcc2) JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 2219 OP 2226 DO 10.1124/dmd.108.021790 VO 36 IS 11 A1 Sonia R. Miranda A1 Jin Kyung Lee A1 Kim L. R. Brouwer A1 Zhiming Wen A1 Philip C. Smith A1 Roy L. Hawke YR 2008 UL http://dmd.aspetjournals.org/content/36/11/2219.abstract AB Silymarin, an extract from seeds of Silybum marianum, is used by 8 to 33% of patients to self-treat chronic viral hepatitis C in the United States. Studies in humans and rodents suggest that biliary excretion of glucuronide and sulfate conjugates is the major route for silymarin's elimination. To determine the role of multidrug resistance-associated protein 2 (Mrp2) (Abcc2) in the biliary excretion of silymarin, the hepatobiliary disposition of the six major silymarin flavonolignans was studied using isolated perfused livers (IPRLs) from wild-type (WT) and Mrp2-deficient (TR-) Wistar rats. For all the flavonolignans, approximately 96% of the dose was cleared from perfusate within 30 min in both WT and TR- livers, and <5% of parent was recovered in bile or perfusate by the end of the perfusion. In WT livers, the percentage of dose excreted as conjugates into bile varied for each flavonolignan (silychristin, 51.6 ± 9.3%; silydianin, 101.5 ± 28.3%; silybin A, 21.0 ± 8.3%; silybin B, 31.7 ± 13.2%; isosilybin A, 50.5 ± 23.6%; isosilybin B, 42.8 ± 19.3%). Among the flavonolignans, only silydianin was primarily glucuronidated and almost completely recovered in bile. In TR- livers, biliary excretion of flavonolignan conjugates was reduced 80 to 92%, with 30 to 83% of each flavonolignan conjugate recovered in perfusate compared with only 5 to 30% at 90 min. Biliary excretion of glucuronide and sulfate conjugates of all the flavonolignans were reduced by 94 to 98% and 73 to 84%, respectively, in TR- IPRLs. These data indicate a primary role for Mrp2 in the biliary elimination of silymarin flavonolignan conjugates. The American Society for Pharmacology and Experimental Therapeutics