Pharmacokinetics of Valerenic Acid in Rats after Intravenous and Oral Administrations

Abstract

Valerenic acid (VA), a sesquiterpenoid, is one of the major secondary bioactive metabolites of Valeriana officinalis L. Until now in vivo studies on the absorption, bioavailability, disposition, and metabolism of VA are limited. We established and validated an LC-MS/MS assay for the determination of VA in rat plasma and successfully used this method for pharmacokinetic studies in rats after intravenous (i. v.) and oral administrations. The plasma concentration-time data was analyzed by both non-compartmental and compartmental approaches using WinNonlin software. Following i. v. administration, the disposition of VA in rat plasma was biphasic, subdivided into a fast distribution and a slow elimination phase. The half-life of the distribution phase was 6–12 min, and that of the terminal elimination phase 6–46 h, indicating a possible large tissue binding. Disposition PK of valerenic acid after oral treatment was also described by a two-compartment model with a clearance (CL/F) of 2–5 L · h⁻¹ · kg⁻¹ and volume of distribution of (V_d) 17–20 L · kg⁻¹. The extent of absorption (F) after oral administration was estimated to be 33.70 % with a half-life of 2.7–5 h. Dose proportionality was observed in terms of dose and AUCs, suggesting linear pharmacokinetics at the dose levels studied in rats.

Key words

Valeriana officinalis - Valerianaceae - valerenic acid - pharmacokinetics - absolute bioavailability - two-compartment model

References

• 1 European Scientific Cooperative on Phytotherapy (ESCOP) . Valeriana officinalis . ESCOP Monographs. 2nd edition. Stuttgart: Thieme; 2003: 539-546
• 2 Khom S, Baburin I, Timin E, Hohaus A, Trauner G, Kopp B, Hering S. Valerenic acid potentiates and inhibits GABA_A receptors: molecular mechanism and subunit specificity.  Neuropharmacology. 2007;  53 178-187
• 3 Khom S, Strommer B, Ramharter J, Schwarz T, Schwarzer C, Erker T, Ecker G F, Mulzer J, Hering S. Valerenic acid derivatives as novel subunit-selective GABAA receptor ligands – in vitro and in vivo characterization.  Br J Pharmacol. 2010;  161 65-78
• 4 Trauner G, Khom S, Baburin I, Benedek B, Hering S, Kopp B. Modulation of GABA_A receptors by valerian extracts is related to the content of valerenic acid.  Planta Med. 2008;  74 19-24
• 5 Neuhaus W, Trauner G, Gruber D, Oelzant S, Klepal W, Kopp B, Noe C R. Transport of a GABAA receptor modulator and its derivatives from Valeriana officinalis L. s. l. across an in vitro cell culture model of the blood-brain barrier.  Planta Med. 2008;  74 1338-1344
• 6 Hendriks H, Bos R, Woerdenbag H J, Koster A S. Central nervous depressant activity of valerenic acid in the mouse.  Planta Med. 1985;  51 28-31
• 7 Murphy K, Kubin Z J, Shepherd J N, Ettinger R H. Valeriana officinalis root extracts have potent anxiolytic effects in laboratory rats.  Phytomedicine. 2010;  17 674-678
• 8 Benke D, Barberis A, Kopp S, Altmann K H, Schubiger M, Vogt K E, Rudolph U, Mohler H. GABA_A receptors as in vivo substrate for the anxiolytic action of valerenic acid, a major constituent of valerian root extracts.  Neuropharmacology. 2009;  56 174-181
• 9 Chow N K, Fretz M, Hamburger M, Butterweck V. Telemetry as a tool to measure sedative effects of a valerian root extract and its single constituents in mice.  Planta Med. 2011;  77 795-803
• 10 Anderson G D, Elmer G W, Taibi D M, Vitiello M V, Kantor E, Kalhorn T F, Howald W N, Barsness S, Landis C A. Pharmacokinetics of valerenic acid after single and multiple doses of valerian in older women.  Phytother Res. 2010;  24 1442-1446
• 11 FDA .Guidance for industry – bioanalytical method validation. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070107.pdf Accessed June 4, 2011
• 12 Barve A, Chen C, Hebbar V, Desiderio, Saw C L, Kong A N. Metabolism, oral bioavailability and pharmacokinetics of chemopreventive kaempferol in rats.  Biopharm Drug Dispos. 2009;  30 356-365
• 13 Davies M, Whitting I J. Numerical methods for non-linear optimization. New York: Academic Press; 1972
• 14 Perry N B, Burgess E J, Lorimer S D, Klink J W. Fatty acid anilides as internal standards for high performance liquid chromatographic analyses of Valerian officinalis L. and other medicinal plants.  Phytochem Anal. 1996;  7 263-268
• 15 Maier-Salamon A, Trauner G, Hiltscher R, Reznicek G, Kopp B, Thalhammer T, Jaeger W. Hepatic metabolism and biliary excretion of valerenic acid in isolated perfused rat livers: role of Mrp2 (Abcc2).  J Pharm Sci. 2009;  98 3839-3849