Abstract
Xuezhikang capsule (XZK) is a traditional Chinese medicine that contains lovastatin (Lv) for hyperlipidemia treatment, although it has fewer side effects than Lv. However, the pharmacokinetic mechanisms contributing to its distinct efficacy and low side effects are unclear. Mice were fed a high-fat diet (HFD) for 6 weeks to induce hyperlipidemia. We first conducted the pharmacokinetic studies in HFD mice following oral administration of Lv (10 mg/kg, i.g.) and found that HFD remarkably decreased the active form of Lv (the lovastatin acid, LvA) exposure in the circulation system, especially in the targeting organ liver, with a declined conversion from Lv to LvA, whereas the Lv (responsible for myotoxicity) exposure in muscle markedly increased. Then we compared the pharmacokinetic profiles of Lv in HFD mice after the oral administration of XZK (1200 mg/kg, i.g.) or an equivalent dose of Lv (10 mg/kg, i.g.). A higher exposure of LvA and lower exposure of Lv were observed after XZK administration, suggesting a pharmacokinetic interaction of some ingredients in XZK. Further studies revealed that HFD promoted the inflammation and inhibited carboxylesterase (CES) activities in the intestine and the liver, thus contributing to the lower transformation of Lv into LvA. In contrast, XZK inhibited the inflammation and upregulated CES in the intestine and the liver. Finally, we evaluated the effects of monacolins and phytosterols, the fractional extracts of isoflavones, on inflammatory LS174T or HepG2 cells, which showed that isoflavones inhibited inflammation, upregulated CES, and markedly enhanced the conversion of Lv into LvA. For the first time, we provide evidence that isoflavones and Lv in XZK act in concert to enhance the efficacy and reduce the side effects of Lv.
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References
Chen ZY, Ma KY, Liang Y, Peng C, Zuo Y. Role and classification of cholesterol-lowering functional foods. J Funct Foods. 2011;3:61–9.
Gropper SS, Smith LJ, Groff LJ. Advanced nutrition and human metabolism. 7th ed. Ohio (USA): Peter Marshall, Wadsworth; 2005.
Ma J, Li Y, Ye Q, Li J, Hua Y, Ju D, et al. Constituents of red yeast rice, a traditional Chinese food and medicine. J Agric Food Chem. 2000;48:5220–5.
Wei W, Li C, Wang Y, Su H, Zhu J, Kritchevsky D. Hypolipidemic and anti-atherogenic effects of long-term Cholestin (Monascus purpureus-fermented rice, red yeast rice) in cholesterol fed rabbits. J Nutr Biochem. 2003;14:314–8.
Lee CL, Tsai TY, Wang JJ, Pan TM. In vivo hypolipidemic effects and safety of low dosage Monascus powder in a hamster model of hyperlipidemia. Appl Microbiol Biotechnol. 2006;70:533–40.
Lin CC, Li TC, Lai MM. Efficacy and safety of Monascus purpureus Went rice in subjects with hyperlipidemia. Eur J Endocrinol. 2005;153:679–86.
Heber D, Yip I, Ashley JM, Elashoff DA, Elashoff RM, Go VL. Cholesterol-lowering effects of a proprietary Chinese red-yeast-rice dietary supplement. Am J Clin Nutr. 1999;69:231–6.
Li C, Zhu Y, Wang Y, Zhu JS, Chang J, Kritchevsky D, et al. Monascus purpureus-fermented rice (red yeast rice): a natural food product that lowers blood cholesterol in animal models of hypercholesterolemia. Nutr Res. 1998;18:71–81.
Wang JJ, Pan TM, Shieh MJ, Hsu CC. Effect of red mold rice supplements on serum and meat cholesterol levels of broilers chicken. Appl Microbiol Biotechnol. 2006;71:812–8.
Liu J, Zhang J, Shi Y, Grimsgaard S, Alraek T, Fønnebø V. Chinese red yeast rice (Monascus purpureus) for primary hyperlipidemia: a meta-analysis of randomized controlled trials. Chin Med. 2006;1:4.
Grieco A, Miele L, Pompili M, Biolato M, Vecchio FM, Grattagliano I, et al. Acute hepatitis caused by a natural lipid-lowering product: when “alternative” medicine is no “alternative” at all. J Hepatol. 2009;50:1273–7.
Klimek M, Wang S, Ogunkanmi A. Safety and efficacy of red yeast rice (Monascus purpureus) as an alternative therapy for hyperlipidemia. P T. 2009;34:313–27.
Heber D, Lembertas A, Lu QY, Bowerman S, Go VL. An analysis of nine proprietary Chinese red yeast rice dietary supplements: implications of variability in chemical profile and contents. J Altern Complement Med. 2001;7:133–9.
Manzoni M, Rollini M. Biosynthesis and biotechnological production of statins by filamentous fungi and application of these cholesterol-lowering drugs. Appl Microbiol Biotechnol. 2002;58:555–64.
Trimarco B, Benvenuti C, Rozza F, Cimmino CS, Giudice R, Crispo S. Clinical evidence of efficacy of red yeast rice and berberine in a large controlled study versus diet. Med J Nutr Metab. 2011;4:133–9.
Shang Q, Liu Z, Chen K, Xu H, Liu J. A systematic review of Xuezhikang, an extract from red yeast rice, for coronary heart disease complicated by dyslipidemia. Evid Based Complement Altern Med. 2012;2012:636547.
Ma KY, Zhang ZS, Zhao SX, Chang Q, Wong YM, Yeung SY, et al. Red yeast rice increases excretion of bile acids in Hamsters. Biomed Environ Sci. 2009;22:269–77.
Becker DJ, Gordon RY, Halbert SC, French B, Morris PB, Rader DJ. Red yeast rice for dyslipidemia in statin-intolerant patients: a randomized trial. Ann Intern Med. 2009;150:830–9.
Bartley GE, Yokoyama W, Young SA, Anderson WH, Hung SC, Albers DR, et al. Hypocholesterolemic effects of hydroxypropyl methylcellulose are mediated by altered gene expression in hepatic bile and cholesterol pathways of male hamsters. J Nutr. 2010;140:1255–60.
Gordon RY, Cooperman T, Obermeyer W, Becker DJ. Marked variability of monacolin levels in commercial red yeast rice products: buyer beware! Arch Intern Med. 2010;170:1722–7.
Kidambi S, Patel S. Cholesterol and non-cholesterol sterol transporters: ABCG5, ABCG8 and NPC1L1: a review. Xenobiotica. 2008;38:1119–39.
Liu ZL, Liu JP, Zhang AL, Wu Q, Ruan Y, Lewith G, et al. Chinese herbal medicines for hypercholesterolemia. Cochrane Database Syst Rev. 2011;7:CD008305.
Wang SR, Effects of Xuezhikang vs lovastatin in treating hyperlipidemia. Chin J New Drugs Clin Remedies. 2000;19:249–51.
Liu LJ, Ma SR, Liu SC. The pharmacological effects and clinical evaluation of Xuezhikang. China. Pharmacy. 2003;14:184–6.
Feng D, Sun JG, Sun RB, Ou-Yang BC, Yao L, Aa JY, et al. Isoflavones and phytosterols contained in Xuezhikang capsules modulate cholesterol homeostasis in high-fat diet mice. Acta Pharmacol Sin. 2015;36:1462–72.
Satoh T, Hosokawa M. The mammalian carboxylesterases: from molecules to functions. Annu Rev Pharmacol Toxicol. 1998;38:257–88.
Furihata T, Hosokawa M, Nakata F, Satoh T, Chiba K. Purification, molecular cloning, and functional expression of inducible liver acylcarnitine hydrolase in C57BL/6 mouse, belonging to the carboxylesterase multigene family. Arch Biochem Biophys. 2003;416:101–9.
Furihata T, Hosokawa M, Koyano N, Nakamura T, Satoh T, Chiba K. Identification of di-(2-ethylhexyl) phthalate-induced carboxylesterase 1 in C57BL/6 mouse liver microsomes: purification, cDNA cloning, and baculovirus-mediated expression. Drug Metab Dispos. 2004;32:1170–7.
Hosokawa M, Suzuki K, Takahashi D, Mori M, Satoh T, Chiba K. Purification, molecular cloning, and functional expression of dog liver microsomal acyl-CoA hydrolase: a member of the carboxylesterase multigene family. Arch Biochem Biophys. 2001;389:245–53.
Heymann E. Hydrolysis of carboxylic esters and amides. In: Jacoby WB, editor. Metabolic basis of detoxication; metabolism of functional groups. New York: Elsevier; 1982. p. p229–45.
Jones RD, Taylor AM, Tong EY, Repa JJ. Carboxylesterases are uniquely expressed among tissues and regulated by nuclear hormone receptors in the mouse. Drug Metab Dispos. 2013;41:40–9.
Halpin RA, Ulm EH, Till AE, Kari PH, Vyas KP, Hunninghake DB, et al. Biotransformation of lovastatin. V. Species differences in in vivo metabolite profiles of mouse, rat, dog, and human. Drug Metab Dispos. 1993;21:1003–11.
Knauer MJ, Urquhart BL, Meyer zu Schwabedissen HE, Schwarz UI, Lemke CJ, Leake BF, et al. Human skeletal muscle drug transporters determine local exposure and toxicity of statins. Circ Res. 2010;106:297–306.
Skottheim IB, Gedde-Dahl A, Hejazifar S, Hoel K, Asberg A. Statin induced myotoxicity: the lactone forms are more potent than the acid forms in human skeletal muscle cells in vitro. Eur J Pharm Sci. 2008;33:317–25.
Shen W, Patel S, Yu Z, Jue D, Kraemer FB. Effects of rosiglitazone and high fat diet on lipase/esterase expression in adipose tissue. Biochim Biophys Acta. 2007;1771:177–84.
Friedrichsen M, Poulsen P, Wojtaszewski J, Hansen PR, Vaag A, Rasmussen HB. Carboxylesterase 1 gene duplication and mRNA expression in adipose tissue are linked to obesity and metabolic function. PLoS ONE. 2013;8:e56861.
Pati S, Krishna S, Lee JH, Ross MK, de La Serre CB, Harn DA Jr, et al. Effects of high-fat diet and age on the blood lipidome and circulating endocannabinoids of female C57BL/6 mice. Biochim Biophys Acta. 2018;1863:26–39.
Steven S, Dib M, Hausding M, Kashani F, Oelze M, Kröller-Schön S, et al. CD40L controls obesity-associated vascular inflammation, oxidative stress and endothelial dysfunction in mice-translational aspects for man. Cardiovasc Res. 2017;121:10552–61.
Jung TW, Kim HC, Abd El-Aty AM, Jeong JH. Protectin DX ameliorates palmitate- or high-fat diet-induced insulin resistance and inflammation through an AMPK-PPARα-dependent pathway in mice. Sci Rep. 2017;7:1397.
Mohammadi M, Gozashti MH, Aghadavood M, Mehdizadeh MR, Hayatbakhsh MM. Clinical significance of serum IL-6 and TNF-α levels in patients with metabolic syndrome. Rep Biochem Mol Biol. 2017;6:74–9.
Richardson TA, Morgan ET. Hepatic cytochrome P450 gene regulation during endotoxin-induced inflammation in nuclear receptor knockout mice. J Pharmacol Exp Ther. 2005;314:703–9.
Wait R, Chiesa GC, Parolini C, Miller I, Begum S, Brambilla D, et al. Reference maps of mouse serum acute-phase proteins: changes with LPS-induced inflammation and apolipoprotein A-I and A-II transgenes. Proteomics. 2005;5:4245–53.
Xiong J, Shang W, Wu L, Chen R, Liu W, Ning R, et al. Glucose dominates the regulation of carboxylesterases induced by lipopolysaccharide or interleukin-6 in primary mouse hepatocytes. Life Sci. 2014;112:41–8.
Li JJ, Hu SS, Fang CH, Hui RT, Miao LF, Yang YJ, et al. Effects of Xuezhikang, an extract of cholestin, on lipid profile and C-reactive protein: a short-term time course study in patients with stable angina. Clin Chim Acta. 2005;352:217–24.
Zanin V, Marcuzzi A, Kleiner G, Piscianz E, Monasta L, Zacchigna S, et al. Lovastatin dose-dependently potentiates the pro-inflammatory activity of lipopolysaccharide both in vitro and in vivo. J Cardiovasc Transl Res. 2013;6:981–8.
Zhao S, Zhang Y, Ju P, Gu L, Zhuang R, Zhao L, et al. Determination of 6258-70, a new semi-synthetic taxane, in rat plasma and tissues: application to the pharmacokinetics and tissue distribution study. J Pharm Anal. 2016;6:219–25.
Lu XF, Bi K, Chen X. Physiologically based pharmacokinetic model of docetaxel and interspecies scaling: comparison of simple injection with folate receptor-targeting amphiphilic copolymer-modified liposomes. Xenobiotica. 2016;46:1093–104.
Wang Q, Chao J, Xiao Z, Zhu X, Yan S, Wang H, et al. Insight into the pharmacokinetic behavior of tanshinone IIA in the treatment of Crohn’s disease: comparative data for tanshinone IIA and its two glucuronidated metabolites in normal and recurrent colitis models after oral administration. Xenobiotica. 2017;47:66–76.
Wang Y, Zhao M, Ye H, Shao Y, Yu Y, Wang M, et al. Comparative pharmacokinetic study of the main components of Cortex Fraxini after oral administration in normal and hyperuricemic rats. Biomed Chromatogr. 2017;31:3934.
Gross V, Treher E, Haag K, Neis W, Wiegand U, Schölmerich J. Angiotensin-converting enzyme (ACE)-inhibition in cirrhosis: pharmacokinetics and dynamics of the ACE-inhibitor cilazapril (Ro 31-2848). J Hepatol. 1993;17:40–7.
Thiollet M, Funck-Brentano C, Grange JD, Midavaine M, Resplandy G, Jaillon P. The pharmacokinetics of perindopril in patients with liver cirrhosis. Br J Clin Pharmacol. 1992;33:326–8.
Hao W, Zhu ZY, Zhang GQ, Zhao L, Zhang H, Zhu D, et al. Comparative pharmacokinetic study of paeoniflorin after oral administration of pure paeoniflorin, extract of cortex Moutan and Shuang-Dan prescription to rats. J Ethnopharmacol. 2009;125:444–9.
Petiwala SM, Li G, Ramaiya A, Kumar A, Gill RK, Saksena S, et al. Pharmacokinetic characterization of mangosteen (Garcinia mangostana) fruit extract standardized to α-mangostin in C57BL/6 mice. Nutr Res. 2014;34:336–45.
Yang M, Yang X, An J, Xiao W, Wang Z, Huang W, et al. Comparative pharmacokinetic profiles of tectorigenin in rat plasma by UPLC-MS/MS after oral administration of Iris tectorum maxim extract and pure tectoridin. J Pharm Biomed Anal. 2015;114:34–41.
Gertz M, Davis JD, Harrison A, Houston JB, Galetin A. Grapefruit juice-drug interaction studies as a method to assess the extent of intestinal availability: utility and limitations. Curr Drug Metab. 2008;9:785–95.
Acknowledgements
The study was financially supported by the National Natural Science Foundation of China (81373481), the Jiangsu Provincial Promotion Foundation for the Key Lab of Drug Metabolism and Pharmacokinetics (Grant No. BM2012012), and the Key Technology Projects of China “Creation of New Drugs” (No. 2015ZX09501001).
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DF contributed to the design and performed most of the experiments; CG analyzed the data and drafted the manuscript; GW and JA contributed to the development of the project and experimental design; ZT, JS, YX, LY, and CY assisted with the experiments; JA reviewed the manuscript. All authors read and approved the final manuscript.
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Feng, D., Ge, C., Tan, Zy. et al. Isoflavones enhance pharmacokinetic exposure of active lovastatin acid via the upregulation of carboxylesterase in high-fat diet mice after oral administration of Xuezhikang capsules. Acta Pharmacol Sin 39, 1804–1815 (2018). https://doi.org/10.1038/s41401-018-0039-1
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DOI: https://doi.org/10.1038/s41401-018-0039-1
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