Advance in Pre-Clinical Pharmacokinetics of Paeoniflorin, a Major Monoterpene Glucoside from the Root of Paeonia lactiflora

Orleans N. K. Martey, Xiaoyan Shi, Xin He

School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China;.
School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China; Centre for Scientific Re-search into Plant Medicine, Akwapim-Mampong, Ghana.
School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China;Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin, China..

DOI: 10.4236/pp.2013.47A1002                

Abstract

Paeoniflorin (PF) is one of the main bioactive components of total glucosides of paeony (TGP) extracted from the root of Paeonia lactiflora Pall. TGP exhibit various biological activities such as improvement in memory, hepatoprotection, antimutagenic properties and platelet aggregation inhibition. The aim of this paper is to review the pharmacokinetics (PK) of PF as a pure compound and in single or multiple herb(s) of traditional Chinese medicine (TCM) prescriptions. The distribution of PF or PF in TCM fitted one or two compartmental model after oral administration or intravenous injection, respectively. However, PF has a low bioavailability (BA) in rabbit (7.24%) and rat (3.24%) after oral administration. The PK profiles and BA of PF were remarkably improved when co-administered with sinomenine or glycyrrhizin acid. The PK profiles and BA of PF in Radix Paeonia Rubra (RP-R) and Jing-zhi guan-xin were improved, but in co-administration of RP-R with Radix Angelicae Sinensis, the BA was significantly reduced. PK profiles and BA of PF in Shan yao gan-cao tang or Danggui-Shaoyao-San was either remarkably improved or not. However, neither the PK profiles nor the BA of PF in Radix paeonia alba, Huangqin-tang Si ni san or Tang-Min-Ling-Wan was improved. Metabolism in the liver did not play any role in the low oral BA of PF. The low BA was thus attributed to poor permeation due to low lipophilicity, P-glycoprotein mediated efflux, intestinal bacteria and hydrolytic degradation in the intestine by the intestinal brush border lactase phlorizin hydrolase (LPH) and certain esterases. These findings show the in vivo course of PF and provide information on the maximum biological actions of PF that may help traditional Chinese herbal medicinal practitioners.

Keywords

Bioavailability; Intestinal Bacteria; Pharmacokinetics; Paeoniflorin (PF); P-glycoprotein (P-gp)

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	“National Institute for the Control of Pharmaceutical and Biological Products,” Color Atlas of Chinese Traditional Drugs, Vol. 1, Science Press, Beijing, 1987.
[2]	J. Y. Geng, W. Q. Huang, T. C. Ren and X. F. Ma, “Medicinal Herbs,” New World Press, Beijing, 1990.
[3]	J. Bruneton, “Pharmacognosy, Phytochemistry, Medicinal Plants,” Lavoisier, Paris, 1995.
[4]	Committee of the Pharmacopoeia of PR China, “Pharmacopoeia of PR China,” Part I. Chemical Industry Press, Beijing, 2010.
[5]	I. N. Kostova, M. F. Simeonov and D. I. Todorova, “A Monoterpene Glucoside from Paeonia peregrina Roots,” Phytochemistry, Vol. 47, No. 7, 1998, pp. 1303-1307. http://dx.doi.org/10.1016/S0031-9422(97)00683-3
[6]	Q. Wang, R. X. Liu, H. L. Yu, P. Liu, Z. T. Liu, K. S. Bi and D. A. Guo, “Studies on HPLC Fingerprint of White Peony Roots and Red Peony Roots,” Chinese Pharmaceutical Journal, Vol. 42, No. 8, 2007, pp. 581-584.
[7]	A. Bracaa, P. V. Kiem, P. H. Yen, N. X. Nhiem, T. H. Quang, N. X. Cuong and C. V. Minh, “New Monoterpene Glycosides from Paeonia lactiflora,” Fitoterapia, Vol. 79, No. 2, 2008, pp. 117-120. http://dx.doi.org/10.1016/j.fitote.2007.11.001
[8]	K. Washida, Y. Itoh, T. Iwashita and K. Nomoto, “Androgen Modulators from the Roots of Paeonia lactiflora (Paeoniae Radix) Grown and Processed in Nara Prefecture,” Chemical & Pharmaceutical Bulletin, Vol. 57, No. 9, 2009, pp. 971-974. http://dx.doi.org/10.1248/cpb.57.971
[9]	K. Washida, T. Yamagaki, T. Iwashita and K. Nomoto, “Two New Galloylated Monoterpene Glycosides, 4-O-Galloylalbiflorin and 4-O-Galloylpaeoniflorin, from the Roots of Paeonia lactiflora (Paeoniae Radix) Grown and Processed in Nara Prefecture,” Chemical & Pharmaceutical Bulletin, Vol. 57, No. 10, 2009, pp. 1150-1152. http://dx.doi.org/10.1248/cpb.57.1150
[10]	J. Yamahara, T. Yamada, H. Kimura, T. Sawada and H. Fujimura, “Biologically Active Principles of Crude Drugs. II. Anti-Allergic Principles in ‘Shoseiryu-To’ Anti-Inflammatory Properties of Paeoniflorin and Its Derivatives,” Journal of Pharmacobio-Dynamics, Vol. 5, No. 11, 1982, pp. 921-929. http://dx.doi.org/10.1248/bpb1978.5.921
[11]	H. Ishida, M. Takamatsu, K. Tsuji and T. Kosuge, “Studies on Active Substances in Herbs Used for Oketsu (‘Stagnant Blood’) in Chinese Medicine on the Anticoagulative Principle in Moutan cortex,” Chemical & Pharmaceutical Bulletin, Vol. 35, No. 2, 1987, pp. 846-848. http://dx.doi.org/10.1248/cpb.35.846
[12]	K. Dezaki, I. Kimura, K. Miyahara and M. Kimura, “Complementary Effects of Paeoniflorin and Glycyrrhizin on Intracellular Ca2+ Mobilization in the Nerve-Stimulated Skeletal Muscle of Mice,” Japanese Journal of Pharmacology, Vol. 69, No, 3, 1995, pp. 281-284. http://dx.doi.org/10.1254/jjp.69.281
[13]	H. Ohta, K. Matsumoto, M. Shimizu and H. Watanabe, “Paeoniflorin Attenuates Learning Impairment of Aged Rats in Operant Brightness Discrimination Task,” Pharmacology Biochemistry and Behavior, Vol. 49, No. 1, 1994, pp. 213-217. http://dx.doi.org/10.1016/0091-3057(94)90478-2
[14]	H. Ohta, J. W. Ni, K. Matsumoto, H. Watanabe and M. Shimizu, “Peony and Its Major Constituent, Paeoniflorin, Improve Radial Maze Performance Impaired by Scopolamine in Rats,” Pharmacology Biochemistry and Behavior, Vol. 45, No. 3, 1993, pp. 719-723. http://dx.doi.org/10.1016/0091-3057(93)90530-7
[15]	K. Tabata, K. Matsumoto and H. Watanabe, “Paeoniflorin a Major Constituent of Peony Root Reverses Muscarinic M1-Receptor Antagonist-Induced Suppression of Long-Term Potentiation in the Rat Hippocampal Slice,” Japanese Journal of Pharmacology, Vol. 83, No. 1, 2000, pp. 25-30. http://dx.doi.org/10.1254/jjp.83.25
[16]	F. L. Hsu, C. W. Lai and J. T. Cheng, “Antihyperglycemic Effects of Paeoniflorin and 8-Debenzoylpaeoniflorin, Glucosides from the Root of Paeonia lactiflora,” Planta Medica, Vol. 63, No. 4, 1997, pp. 323-325. http://dx.doi.org/10.1055/s-2006-957692
[17]	D. Z. Liu, K. Q. Xie, X. Q. Ji, Y. Ye, C. L. Jiang and X. Z. Zhu, “Neuroprotective Effect of Paeoniflorin on Cerebral Ischemic Rat by Activating Adenosine A1 Receptor in a Manner Different from Its Classical Agonists,” British Journal of Pharmacology, Vol. 146, No. 4, 2005, pp. 604-611. http://dx.doi.org/10.1038/sj.bjp.0706335
[18]	C. L. Hsieh, C. Y. Cheng, T. H. Tsai, I. H. Lin, C. H. Liu, S. Y. Chiang, et al., “Paeonol Reduced Cerebral Infarction Involving the Superoxideanion and Microglia Activation in Ischemia-Reperfusion Injured Rats,” Journal of Ethnopharmacology, Vol. 106, No. 2, 2006, pp. 208-215. http://dx.doi.org/10.1016/j.jep.2005.12.027
[19]	C. Chen, Y. Zhang, J. Chen and J. Li, “The Studies on Pharmacokinetics of Paeoniflorin,” Chinese Pharmacological Bulletin, Vol. 5, 1990, pp. 299-302.
[20]	G. L. Chen, C. H. Chen and S. Y. Xu, “The Studies on Pharmacokinetics of Paeoniflorin in Rabbits and Rats,” Chinese Pharmacological Bulletin, Vol. 4, 1992, pp. 278-280.
[21]	S. Takeda , T. Isono , Y. Wakui , Y. Matsuzaki, H. Sasaki, S. Amagaya and M. Maruno, “Absorption and Excretion of Paeoniflorin in Rats,” Journal of Pharmacy and Pharmacology, Vol. 47, No. 12A, 1995, pp. 1036-1340. http://dx.doi.org/10.1111/j.2042-7158.1995.tb03293.x
[22]	C. H. Wang, R. Wang, X. M. Cheng, Y. Q. He, Z. T. Wang, C. Wu and J. Cao, “Comparative Pharmacokinetic Study of Paeoniflorin after Oral Administration of Decoction of Radix Paeoniae Rubra and Radix Paeoniae Alba in Rats,” Journal of Ethnopharmacology, Vol. 117, No. 3, 2008, pp. 467-472. http://dx.doi.org/10.1016/j.jep.2008.02.035
[23]	Y. F. Li, M. Wang, X. Y. Wang, H. S. Yu, L. P. Kang, B. P. Ma, J. X. Ruan and Z. Q. Zhang, “Pharmacokinetic Properties of Albiflorin and Paeoniflorin after Oral Administration of Pure Compound, Radix Paeoniae Alba Extract and Danggui-Shaoyao-San Extract to Rats,” Journal of Asian Natural Products Research, Vol. 13, No. 2, 2011, pp. 117-127. http://dx.doi.org/10.1080/10286020.2010.546353
[24]	S. Takeda, T. Isono, Y. Wakui, Y. Mizuhara, S. Amagaya, M. Maruno and M. Hattori, “In Vivo Assessment of Extrahepatic Metabolism of Paeoniflorin in Rats: Relevance to Intestinal Floral Metabolism,” Journal of Pharmacy and Pharmacology, Vol. 49, No, 1, 1997, pp. 35-39. http://dx.doi.org/10.1111/j.2042-7158.1997.tb06748.x
[25]	M. Hattori, Y. Z. Shu, M. Shimizu, T. Hayashi, N. Morita, K. Kobashi, G. J. Xu and T. Namba, “Metabolism of Paeoniflorin and Related Compounds by Human Intestinal Bacteria,” Chemical and Pharmaceutical Bulletin, Vol. 33, No. 9, 1985, pp. 3838-3846. http://dx.doi.org/10.1248/cpb.33.3838
[26]	F. Zuo, Z. M. Zhou, Q. Zhang, D. Mao, Y. L. Xiong, Y. L. Wang, M. Z. Yan and M. L. Liu, “Pharmacokinetic Study on the Multi-Constituents of Huangqin-Tang Decoction in Rats,” Biological & Pharmaceutical Bulletin, Vol. 26, No. 7, 2003, pp. 911-919. http://dx.doi.org/10.1248/bpb.26.911
[27]	Z. Q. Liu, Z. H. Jiang, L. Liu and M. Hu, “Mechanisms Responsible for Poor Oral Bioavailability of Paeoniflorin: Role of Intestinal Disposition and Interactions with Sinomenine,” Pharmaceutical Research, Vol. 23, No. 12, 2006, pp. 2768-2780. http://dx.doi.org/10.1007/s11095-006-9100-8
[28]	J. F. Ye, H. L. Duan, X. M. Yang, W. Yan and X. Zheng, “Anti-Thrombosis Effect of Paeoniflorin: Evaluated in a Photochemical Reaction Thrombosis Model in Vivo,” Planta Medica, Vol. 67, No. 8, 2001, pp. 766-767. http://dx.doi.org/10.1055/s-2001-18364
[29]	Y. M. Wu, H. P. Xu, C. T. Wang, H. Yang and G. Ju, “Protective Effects of Paeoniflorin on Cultured Cortical Neurons of Mice,” Chinese Journal of Pharmacology and Toxicology, Vol. 16, No. 3, 2002, pp. 172-175.
[30]	R. Wang, “A Comparison on Pharmacological Actions between Radix Paeoniae Rubra and Radix Paeoniae Alba,” China Journal of Experimental Traditional Medical Formulae, Vol. 16, No. 7, 2010, pp. 112-114.
[31]	H. Z. Wu and N. S. Xiong, “Pharmacological Research and Clinical Application of Radix Paeoniae Alba,” Chinese Journal of Hospital Pharmacy, Vol. 18, No. 4, 1988, p. 172.
[32]	C. Feng, M. Liu, X. Shi, W. Yang, D. Kong, K. Duan and Q. Wang, “Pharmacokinetic Properties of Paeoniflorin, Albiflorin and Oxypaeoniflorin after Oral Gavage of Extracts of Radix Paeoniae Rubra and Radix Paeoniae Alba in Rats,” Journal of Ethnopharmacology, Vol. 130, No. 2, 2010, pp. 407-413. http://dx.doi.org/10.1016/j.jep.2010.05.028
[33]	J. Wu, N. Yao and D. W. Wang, “Determination of Paeoniflorin in Rat Plasma by HPLC-MS/MS and Its Pharmacokinetics,” China Journal of Chinese Material Medica, Vol. 33, No. 20, 2008, pp. 2369-2273.
[34]	T. Bao, Q. Yang, Y. Zhang, Y. Dong, Y. Li and X. Zhu, “Pharmacokinetics Study on Paeoniflorin in Radix Paeoniae Alba Extract by LC-MS,” China Journal of Chinese Material Medica, Vol. 35, No. 9, 2010, pp. 1193-1196.
[35]	F. Jiang, Y. Zhao, J. Wang , S. Wei, Z. Wei, R. Li, Y. Zhu, Z. Sun and X. Xiao, “Comparative Pharmacokinetic Study of Paeoniflorin and Albiflorin after Oral Administration of Radix Paeoniae Rubra in Normal Rats and the Acute Cholestasis Hepatitis Rats,” Fitoterapia, Vol. 83, No. 2, 2012, pp. 415-421. http://dx.doi.org/10.1016/j.fitote.2011.12.009
[36]	Y. Tanaka, L. M. Aleksunes, Y. J. Cui and C. D. Klaassen, “ANIT-Induced Intrahepatic Cholestasis Alters Hepatobiliary Transporter Expression via Nrf2-Dependent and Independent Signaling,” Toxicological Sciences, Vol. 108, No. 2, 2009, pp. 247-257. http://dx.doi.org/10.1093/toxsci/kfp020
[37]	Y. Ohta, M. Kongo-Nishimura, T. Hayashi, A. Kitagawa, T. Matsura and K. J. Yamada, “Saikokeishito Extract Exerts a Therapeutic Effect on Alpha-Naphthylisothiocyanate-Induced Liver Injury in Rats through Attenuation of Enhanced Neutrophil Infiltration and Oxidative Stress in the Liver Tissue,” Journal of Clinical Biochemistry and Nutrition, Vol. 40, No. 1, 2007, pp. 31-41. http://dx.doi.org/10.3164/jcbn.40.31
[38]	X. He, D. Xing, Y. Ding, Y. Li, L. Xu and L. Du, “Effects of Cerebral Ischemia-Reperfusion on Pharmacokineticfate of Paeoniflorin after Intravenous Administration of Paeoniae Radix Extract in Rats,” Journal of Ethnopharmacology, Vol. 94, No. 2, 2004, pp. 339-344. http://dx.doi.org/10.1016/j.jep.2004.06.009
[39]	L. C. Chen, M. H. Chou, M. F. Lin and L. L. Yang, “Pharmacokinetics of Paeoniflorin after Oral Administration of Shaoyao Gancao Tang in Mice,” Japanese Journal of Pharmacology, Vol. 88, No.3, 2002, pp. 250-255. http://dx.doi.org/10.1254/jjp.88.250
[40]	L. Shen, R. W. Hu , X. Lin, W. J. Cong, Y. L. Hong, Y. Feng, D. S. Xu and K. F. Ruan, “Pharmacokinetics of Characteristic Effective Ingredients from Individual and Combination Shaoyao and Gancao Treatement in Rats Using HPLC Fingerprinting,” European Journal of Drug Metabolism and Pharmacokinetics, Vol. 37, No. 2, 2011. pp. 133-140. http://dx.doi.org/10.1007/s13318-011-0052-y
[41]	P. Gan, M. Zhong, X. Huang, M. Sun, Y. Wang, Y. Xiao, et al., “Pharmacokinetic Comparisons of Albiflorin and Paeoniflorin after Oral Administration of Shaoyao Gacao-Tang and Single Herb Paeony Decoction to Rats,” Planta Medica, Vol. 78, No. 3, 2012, pp. 237-243. http://dx.doi.org/10.1055/s-0031-1280366
[42]	X. G. Yang, B. Peng, G. H. Zhang, L. L. Wei, S. F. Nie and W. S. Pan, “Studies of the Pharmacokinetics of Paeoniflorin in Two Jing-Zhi-Guan-Xin Formulations after Oral Administration to Beagle Dogs,” Journal of Pharmaceutical and Biomedical Analysis, Vol. 41, No. 1, 2006, pp. 320-324. http://dx.doi.org/10.1016/j.jpba.2005.11.004
[43]	J. Liu, J. S. Wang and L. Y. Kong, “Comparative Pharmacokinetics of Paeoniflorin in Plasma of Vascular Dementia and Normal Rats Orally Administrated with Danggui-Shaoyao-San or Pure Paeoniflorin,” Fitoterapia, Vol. 82, No. 3, 2011, pp. 466-473. http://dx.doi.org/10.1016/j.fitote.2010.12.004
[44]	D. F. Liu, L. Zhang and T. Chen, “Pharmacokinetics Study on Paeoniflorin in Sini Sanghai,” China Journal of Experimental Traditional Medical Formulae, Vol. 11, No. 2, 2005, pp. 36-38.
[45]	L. Tong, M. Wan, D. Zhou, J. Gao, Y. Zhu and K. Bi, “LC-MS/MS Determination and Pharmacokinetic Study of Albiflorin and Paeoniflorin in Rat Plasma after Oral Administration of Radix Paeoniae Alba Extract and Tang-Min-Ling-Wan,” Biomedical Chromatography, Vol. 24, No. 12, 2010, pp. 1324-1331. http://dx.doi.org/10.1002/bmc.1443
[46]	Y. H. Hwang, T. Kim, W. K. Cho, D. Jang, J. H. Ha and J. Y. Ma, “Food-and Gender-Dependent Pharmacokinetics of Paeoniflorin after Oral Administration with Samul-Tang in Rats,” Journal of Ethnopharmacology, Vol. 142, No. 1, 2012, pp. 161-167. http://dx.doi.org/10.1016/j.jep.2012.04.032
[47]	Q. Wang, “Yilin Gaicuo,” People’s Medical Publishing House, Beijing, 2005.
[48]	J. Zhang, G. Yang, R. Lin and Z. Hu, “Determination of Paeoniflorin, Calycosin-7-O-β-D-glucoside, Ononin, Calycosin and Formononetin in Rat Plasma after Oral Administration of Buyang Huanwu Decoction for Their Pharmacokinetic Study by Liquid Chromatography-Mass Spectrometry,” Biomedical Chromatography, Vol. 25, No. 4, 2011, pp. 450-457. http://dx.doi.org/10.1002/bmc.1466
[49]	J. Yuan, Y. Wang, A. Rui, S. Wang, S. J. Li, J. Y. Jia, A. S. W. Bligh, X. H. Wang and Y. M. Ma, “Simultaneous Determination of Six Alkaloids and One Monoterpene in Rat Plasma by Liquid Chromatography-Tandem Mass Spectrometry and Pharmacokinetic Study after Oral Administration of a Chinese Medicine Wuji Pill,” Journal of Chromatography B, Vol. 895-896, 2012, pp. 154-161.
[50]	R. Bouer, L. Barthe, C. Philibert, C. Tournaire, J. Woodley and G. Houin, “The Role of P-Glycorprotein and Intracellular Metabolism in the Intestinal Absorption of Methadone: In Vitro Studies Using the Rat Everted Intestinal Sac,” Fundamental & Clinical Pharmacology, Vol. 13, No. 4, 1999, pp. 494-500. http://dx.doi.org/10.1111/j.1472-8206.1999.tb00009.x
[51]	K. Chan, Z. Q. Liu, Z. H. Jiang, H. Zhou, Y. F. Wong, H. X. Xu and L. Liu, “The Effects of Sinomenine on Intestinal Absorption of Paeoniflorin by the Everted Rat Gut Sac Model,” Journal of Ethnopharmacology, Vol. 103, No. 3, 2006, pp. 425-432. http://dx.doi.org/10.1016/j.jep.2005.08.020
[52]	Q. L. Zhong, Z. Hua, L. Liang, H. J. Zhi, F. W. Yuen, X. Ying, C. Xiong, X. X. Hong and C. Kelvin, “Influence of Co-Administrated Sinomenine on Pharmacokinetic Fate of Paeoniflorin in Unrestrained Conscious Rats,” Journal of Ethnopharmacology, Vol. 99, No. 1, 2005, pp. 61-67. http://dx.doi.org/10.1016/j.jep.2005.01.052
[53]	L. Shen, L. Zhang, Y. Feng, D. S. Xu and X. Lin, “Pharmacokinetics of Paeonia lactiflora and G lycyrrhiza uralensis Compound, ” Chinese Traditional Patent Medicine, Vol. 31, No. 3, 2009, pp. 374-377.
[54]	E. Liang, J. Proudfoot and M. Yazdanian, “Mechanisms of Transport and Structure of Permeability Relationship of Sulfasala-Zine and Its Analogs in Caco-2 Cell Monolayers,” Pharmaceutical Research, Vol. 17, No. 10, 2000, pp.1168-1174. http://dx.doi.org/10.1023/A:1026450326712
[55]	E. J. Jeong, Y. Liu, H. Lin and M. Hu, “In Situ Single-Pass Perfused Rat Intestinal Model for Absorption and Metabolism,” In: N. J. Totowa, Ed., Optimization in Drug Discovery: In Vitro Methods, Springer, Berlin, 2004, pp. 65-76. http://dx.doi.org/10.1385/1-59259-800-5:065
[56]	Y. Liu, Y. Liu, Y. Dai, L. Y. Xun and M. Hu, “Enteric Disposition and Recycling of Flavonoids and Ginkgo Flavonoids,” Journal of Alternative and Complementary Medicine, Vol. 9, No. 5, 2003, pp. 631-640.