Flavonoid Pharmacokinetics and Tissue Distribution after Repeated Dosing of the Roots of Scutellaria baicalensis in Rats

Abstract

Scutellariae Radix (root of Scutellaria baicalensis, SR) contains numerous flavonoids such as baicalin, baicalein, and wogonin. This study investigated the pharmacokinetics and tissue distribution of flavonoids and their metabolites in rats after repeated dosing of a SR decoction. Sprague-Dawley rats were orally administered SR at 2 g/kg for seven doses. After the 7th dose, blood samples were withdrawn at specific times and organs, including the liver, kidney, lung, and brain, and collected. The concentrations of baicalein and wogonin in the serum and various tissues were assayed by HPLC before and after hydrolysis with glucuronidase and sulfatase. Baicalein and wogonin were not detected in the serum, and the molecules found were their glucuronides/sulfates. In tissues, the free forms of baicalein and wogonin appeared in the liver, kidney, and lung in addition to their glucuronides/sulfates. Baicalein was the major form in the lung, whereas baicalein glucuronides/sulfates were the major forms in the liver and kidney. Wogonin was the major form in the liver, kidney, lung, and traces of wogonin glucuronides/sulfates were detected in the kidney and liver. Neither baicalein and wogonin nor their glucuronides/sulfates were detected in the brain. In conclusion, the glucuronides/sulfates of baicalein and wogonin were exclusively present in the circulation, whereas their free forms appeared in the lung, liver, and kidney.

Scutellaria baicalensis - Labiatae - pharmacokinetics - tissue distribution - baicalein - wogonin

References

• 1 Kim E H, Shim B, Kang S, Jeong G, Lee J S, Yu Y B, Chun M. Anti-inflammatory effects of Scutellaria baicalensis extract via suppression of immune modulators and MAP kinase signaling molecules.  J Ethnopharmacol. 2009;  126 320-331
• 2 Yoon S B, Lee Y J, Park S K, Kim H C, Bae H, Kim H M, Ko S G, Choi H Y, Oh M S, Park W. Anti-inflammatory effects of Scutellaria baicalensis water extract on LPS-activated RAW 264.7 macrophages.  J Ethnopharmacol. 2009;  125 286-290
• 3 Tseng Y P, Wu Y C, Leu Y L, Yeh S F, Chou C K. Scutellariae Radix suppresses hepatitis B virus production in human hepatoma cells.  Front Biosci (Elite Ed). 2010;  2 1538-1547
• 4 Ikemoto S, Sugimura K, Yoshida N, Yasumoto R, Wada S, Yamamoto K, Kishimoto T. Antitumor effects of Scutellariae Radix and its components baicalein, baicalin, and wogonin on bladder cancer cell lines.  Urology. 2000;  55 951-955
• 5 Kumagai T, Müller C I, Desmond J C, Imai Y, Heber D, Koeffler H P. Scutellaria baicalensis, a herbal medicine: anti-proliferative and apoptotic activity against acute lymphocytic leukemia, lymphoma and myeloma cell lines.  Leuk Res. 2007;  31 523-530
• 6 Wu J A, Attele A S, Zhang L, Yuan C S. Anti-HIV activity of medicinal herbs: usage and potential development.  Am J Chin Med. 2001;  29 69-81
• 7 Ma S C, Du J, But P P, Deng X L, Zhang Y W, Ooi V E, Xu H X, Lee S H, Lee S F. Antiviral Chinese medicinal herbs against respiratory syncytial virus.  J Ethnopharmacol. 2002;  79 205-211
• 8 Chu M, Chu Z Y, Wang D D. The extract of compound Radix Scutellariae on mRNA replication and IFN expression of influenza virus in mice.  Zhong Yao Cai. 2007;  30 63-65
• 9 Yang L P, Sun H L, Wu L M, Guo X J, Dou H L, Tso M O, Zhao L, Li S M. Baicalein reduces inflammatory process in a rodent model of diabetic retinopathy.  Invest Ophthalmol Vis Sci. 2009;  50 2319-2327
• 10 Hsieh C J, Hall K, Ha T, Li C, Krishnaswamy G, Chi D S. Baicalein inhibits IL-1beta- and TNF-alpha-induced inflammatory cytokine production from human mast cells via regulation of the NF-kappaB pathway.  Clin Mol Allergy. 2007;  5 5
• 11 Shao Z H, Vanden Hoek T L, Qin Y, Becker L B, Schumacker P T, Li C Q, Dey L, Barth E, Halpern H, Rosen G M, Tuan C S. Baicalein attenuates oxidant stress in cardiomyocytes.  Am J Physiol Heart Circ Physiol. 2002;  282 H999-H1006
• 12 Huang W H, Lee A R, Yang C H. Antioxidative and anti-inflammatory activities of polyhydroxyflavonoids of Scutellaria baicalensis GEORGI.  Biosci Biotechnol Biochem. 2006;  70 2371-2380
• 13 Kimata M, Shichijo M, Miura T, Serizawa I, Inagaki N, Nagai H. Effects of luteolin, quercetin and baicalein on immunoglobulin E-mediated mediator release from human cultured mast cells.  Clin Exp Allergy. 2000;  30 501-508
• 14 Huang R L, Chen C C, Huang H L, Chang C G, Chen C F, Chang C, Hsieh M T. Anti-hepatitis B virus effects of wogonin isolated from Scutellaria baicalensis.  Planta Med. 2000;  66 694-698
• 15 Chan F L, Choi H L, Chen Z Y, Chan P S, Huang Y. Induction of apoptosis in prostate cancer cell lines by a flavonoid, baicalin.  Cancer Lett. 2000;  160 219-228
• 16 Himeji M, Ohtsuki T, Fukazawa H, Tanaka M, Yazaki S, Ui S, Nishio K, Yamamoto H, Tasaka K, Mimura A. Difference of growth-inhibitory effect of Scutellaria baicalensis-producing flavonoid wogonin among human cancer cells and normal diploid cell.  Cancer Lett. 2007;  245 269-274
• 17 Lai M Y, Hsiu S L, Tsai S Y, Hou Y C, Chao P D. Comparison of metabolic pharmacokinetics of baicalin and baicalein in rats.  J Pharm Pharmacol. 2003;  55 205-209
• 18 Lai M Y, Hsiu S L, Chen C C, Hou Y C, Chao P D. Urinary pharmacokinetics of baicalein, wogonin and their glycosides after oral administration of Scutellariae Radix in humans.  Biol Pharm Bull. 2003;  26 79-83
• 19 O'Leary K A, Day A J, Needs P W, Sly W S, O'Brien N M, Williamson G. Flavonoid glucuronides are substrates for human liver beta-glucuronidase.  FEBS Lett. 2001;  503 103-106
• 20 Pasqualini J R, Chetrite G S. Recent insight on the control of enzymes involved in estrogen formation and transformation in human breast cancer.  J Steroid Biochem Mol Biol. 2005;  93 221-236
• 21 Reed M J, Purohit A, Woo L W, Newman S P, Potter B V. Steroid sulfatase: molecular biology, regulation, and inhibition.  Endocr Rev. 2005;  26 171-202
• 22 de Boer V C, Dihal A A, van der Woude H, Arts I C, Wolffram S, Alink G M, Rietjens I M, Keijer J, Hollman P C. Tissue distribution of quercetin in rats and pigs.  J Nutr. 2005;  135 1718-1725
• 23 Peng H W, Cheng F C, Huang Y T, Chen C F, Tsai T H. Determination of naringenin and its glucuronide conjugate in rat plasma and brain tissue by high-performance liquid chromatography.  J Chromatogr B Biomed Sci Appl. 1998;  714 369-374
• 24 Prasain J K, Jones K, Brissie N, Moore R, Wyss J M, Barnes S. Identification of puerarin and its metabolites in rats by liquid chromatography-tandem mass spectrometry.  J Agric Food Chem. 2004;  52 3708-3712
• 25 Datla K P, Christidou M, Widmer W W, Rooprai H K, Dexter D T. Tissue distribution and neuroprotective effects of citrus flavonoid tangeretin in a rat model of Parkinson's disease.  Neuroreport. 2001;  12 3871-3875
• 26 Coldham N G, Sauer M J. Pharmacokinetics of [¹⁴C]genistein in the rat: gender-related differences, potential mechanisms of biological action, and implications for human health.  Toxicol Appl Pharmacol. 2000;  164 206-215
• 27 Chang H C, Churchwell M I, Delclos K B, Newbold R R, Doerge D R. Mass spectrometric determination of genistein tissue distribution in diet-exposed Sprague-Dawley rats.  J Nutr. 2000;  130 1963-1970
• 28 Abd El Mohsen M M, Kuhnle G, Rechner A R, Schroeter H, Rose S, Jenner P, Rice-Evans C A. Uptake and metabolism of epicatechin and its access to the brain after oral ingestion.  Free Radic Biol Med. 2002;  33 1693-1702
• 29 Youdim K A, Shukitt-Hale B, Joseph J A. Flavonoids and the brain: interactions at the blood-brain barrier and their physiological effects on the central nervous system.  Free Radic Biol Med. 2004;  37 1683-1693
• 30 Ono K, Nakane H. Mechanisms of inhibition of various cellular DNA and RNA polymerases by several flavonoids.  J Biochem. 1990;  108 609-613

1 These authors contributed equally to the study.