Hepatic Metabolism and Biliary Excretion of Valerenic Acid in Isolated Perfused Rat Livers: Role of Mrp2 (Abcc2)

The study was designed to investigate the hepatic metabolism and transport system of valerenic acid, a main active constituent of valerian, in isolated perfused livers from Wistar and Mrp2-deficient TR− rats. After administration of 20 µM valerenic acid, the formation of seven valerenic acid glucuronides (M1-M7), namely two glucuronides of valerenic acid (M6, M7), four glucuronides of hydroxylated valerenic acid (M1, M3, M4, M5), and one glucuronide of hydroxylated dehydro-valerenic acid (M2) in bile and perfusate was quantified by HPLC. The hepatic extraction ratio and clearance of valerenic acid were very high in Wistar and TR− rats (E: 0.983 ± 0.006 vs. 0.981 ± 0.004; Cl: 35.4 ± 0.21 mL/min vs. 35.3 ± 0.14 mL/min). However, biliary excretion and efflux of conjugates differed greatly in TR− rats. While cumulative biliary excretion of unconjugated valerenic acid and the glucuronides M1-M7 dropped dramatically to 1-9%, their efflux into perfusate increased 1.5- to 10-fold. This indicates that valerenic acid and its glucuronides are eliminated into bile by Mrp2. In summary, valerenic acid was metabolized to several conjugates, whereby the canalicular transporter Mrp2 mediated biliary excretion of the parent drug and its glucuronides. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3839-3849, 2009