Metabolism and Pharmacokinetics of a Novel Polyphenol Fatty Acid Ester Phloridzin Docosahexaenoate in Balb/c Female Mice

Overview

Journal Sci Rep

Specialty Science

Date 2020 Dec 8

PMID 33288802

Citations 1

Authors

Wasundara Fernando

Kerry B Goralski

David W Hoskin

H P Vasantha Rupasinghe

Affiliations

Soon will be listed here.

Abstract

Flavonoids are known to undergo phase II metabolism and produce metabolites with similar or stronger biological effects compared to the parent flavonoids. However, the limited cellular uptake and bioavailability restrict their clinical use. We synthesized phloridzin docosahexaenoate (PZ-DHA), a novel fatty acid ester of polyphenol, through an acylation reaction with the aim of increasing the cellular availability and stability of the parent biomolecules, phloridzin (PZ) and docosahexaenoic acid (DHA). Here, we report metabolites and pharmacokinetic parameters of PZ-DHA, determined using ultra-high-performance liquid chromatography-electrospray ionization tandem mass spectrometry. PZ-DHA was taken-up by human (MDA-MB-231, MDA-MB-468, and MCF-7) and mouse (4T1) mammary carcinoma and human non-malignant mammary epithelial cells (MCF-10A) in cellular uptake assays. Our results suggested that the acylation improves the cellular uptake of PZ and stability of DHA within cells. In mouse hepatic microsomal assays, two major glucuronides of PZ-DHA, PZ-DHA-4-O-glucuronide and PZ-DHA-4'-O-glucuronide (MW = 923.02 g/mol), were detected. One tri-methylated- (4,4',6'-O-trimethyl-PZ-DHA) (MW = 788.88 g/mol) and one di-sulphated- (PZ-DHA-4,4'-O-disulphide) PZ-DHA metabolite (MW = 906.20 g/mol) were also identified. Intraperitoneal injections of PZ-DHA (100 mg/kg) into Balb/c female mice was rapidly absorbed with a serum C and T of 23.7 µM and 60 min, respectively, and rapidly eliminated (t = 28.7 min). PZ-DHA and its metabolites are readily distributed throughout the body (V = 57 mL) into many organs. We identified in vitro and in vivo metabolites of PZ-DHA, which could be tested for potential use to treat diseases such as cancer in multiple organ systems.

Citing Articles

Suppression of NNK Metabolism by Anthocyanin-Rich Haskap Berry Supplementation Through Modulation of P450 Enzymes.

Amararathna M, Hoskin D, Goralski K, Rupasinghe H Pharmaceuticals (Basel). 2025; 17(12.

PMID: 39770457 PMC: 11728747. DOI: 10.3390/ph17121615.

Uptake and Transport of Naringenin and Its Antioxidant Effects in Human Intestinal Epithelial Caco-2 Cells.

Zhang Z, Tao Q, Qin Z, Liu X, Li S, Bai L Front Nutr. 2022; 9:894117.

PMID: 35685871 PMC: 9173001. DOI: 10.3389/fnut.2022.894117.

References

Walle T . Absorption and metabolism of flavonoids. Free Radic Biol Med. 2004; 36(7):829-37. DOI: 10.1016/j.freeradbiomed.2004.01.002. View

Ziaullah , Bhullar K, Warnakulasuriya S, Rupasinghe H . Biocatalytic synthesis, structural elucidation, antioxidant capacity and tyrosinase inhibition activity of long chain fatty acid acylated derivatives of phloridzin and isoquercitrin. Bioorg Med Chem. 2012; 21(3):684-92. DOI: 10.1016/j.bmc.2012.11.034. View

Jancova P, Anzenbacher P, Anzenbacherova E . Phase II drug metabolizing enzymes. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2010; 154(2):103-16. DOI: 10.5507/bp.2010.017. View

Hassan M, Sallam H, Hassan Z . The Role of Pharmacokinetics and Pharmacodynamics in Early Drug Development with reference to the Cyclin-dependent Kinase (Cdk) Inhibitor - Roscovitine. Sultan Qaboos Univ Med J. 2011; 11(2):165-78. PMC: 3121020. View

Barr J, Tran T, Rock B, Wahlstrom J, Dahal U . Strain-Dependent Variability of Early Discovery Small Molecule Pharmacokinetics in Mice: Does Strain Matter?. Drug Metab Dispos. 2020; 48(8):613-621. DOI: 10.1124/dmd.120.090621. View

Park H, Lawrence P, Engel M, Kothapalli K, Brenna J . Metabolic fate of docosahexaenoic acid (DHA; 22:6n-3) in human cells: direct retroconversion of DHA to eicosapentaenoic acid (20:5n-3) dominates over elongation to tetracosahexaenoic acid (24:6n-3). FEBS Lett. 2016; 590(18):3188-94. PMC: 5039098. DOI: 10.1002/1873-3468.12368. View

Canuto R, Biocca M, Muzio G, DIANZANI M . Fatty acid composition of phospholipids in mitochondria and microsomes during diethylnitrosamine carcinogenesis in rat liver. Cell Biochem Funct. 1989; 7(1):11-9. DOI: 10.1002/cbf.290070104. View

Richmond W, Wogan M, Isbell J, Gordon W . Interstrain differences of in vitro metabolic stability and impact on early drug discovery. J Pharm Sci. 2010; 99(11):4463-8. DOI: 10.1002/jps.22179. View

Ishisaka A, Mukai R, Terao J, Shibata N, Kawai Y . Specific localization of quercetin-3-O-glucuronide in human brain. Arch Biochem Biophys. 2014; 557:11-7. DOI: 10.1016/j.abb.2014.05.025. View

10.

Brand A, Bauer N, Hallott A, Goldbaum O, Ghebremeskel K, Reifen R . Membrane lipid modification by polyunsaturated fatty acids sensitizes oligodendroglial OLN-93 cells against oxidative stress and promotes up-regulation of heme oxygenase-1 (HSP32). J Neurochem. 2010; 113(2):465-76. DOI: 10.1111/j.1471-4159.2010.06611.x. View

11.

Lukas G, BRINDLE S, Greengard P . The route of absorption of intraperitoneally administered compounds. J Pharmacol Exp Ther. 1971; 178(3):562-4. View

12.

Omiecinski C, Vanden Heuvel J, Perdew G, Peters J . Xenobiotic metabolism, disposition, and regulation by receptors: from biochemical phenomenon to predictors of major toxicities. Toxicol Sci. 2010; 120 Suppl 1:S49-75. PMC: 3145385. DOI: 10.1093/toxsci/kfq338. View

13.

Hung W, Chang W, Lu W, Wei G, Wang Y, Ho C . Pharmacokinetics, bioavailability, tissue distribution and excretion of tangeretin in rat. J Food Drug Anal. 2018; 26(2):849-857. PMC: 9322208. DOI: 10.1016/j.jfda.2017.08.003. View

14.

Bolli A, Marino M, Rimbach G, Fanali G, Fasano M, Ascenzi P . Flavonoid binding to human serum albumin. Biochem Biophys Res Commun. 2010; 398(3):444-9. DOI: 10.1016/j.bbrc.2010.06.096. View

15.

Tamiya-Koizumi K, Koizumi K, Ishihara H, Kojima K . Lipid composition of the plasma membrane isolated from hyperplastic nodules of rat liver. J Biochem. 1985; 97(3):773-9. DOI: 10.1093/oxfordjournals.jbchem.a135117. View

16.

Serafim V, Tiugan D, Andreescu N, Mihailescu A, Paul C, Velea I . Development and Validation of a LC⁻MS/MS-Based Assay for Quantification of Free and Total Omega 3 and 6 Fatty Acids from Human Plasma. Molecules. 2019; 24(2). PMC: 6359656. DOI: 10.3390/molecules24020360. View

17.

Zhang L, Ren T, Wang Z, Wang R, Chang J . Comparative study of the binding of 3 flavonoids to the fat mass and obesity-associated protein by spectroscopy and molecular modeling. J Mol Recognit. 2017; 30(6). DOI: 10.1002/jmr.2606. View

18.

Mantso T, Trafalis D, Botaitis S, Franco R, Pappa A, Rupasinghe H . Novel Docosahexaenoic Acid Ester of Phloridzin Inhibits Proliferation and Triggers Apoptosis in an In Vitro Model of Skin Cancer. Antioxidants (Basel). 2018; 7(12). PMC: 6316153. DOI: 10.3390/antiox7120188. View

19.

Shin S, Kim J, Lee J, Son Y, Lee M, Kim H . Docosahexaenoic acid-mediated protein aggregates may reduce proteasome activity and delay myotube degradation during muscle atrophy in vitro. Exp Mol Med. 2017; 49(1):e287. PMC: 5291838. DOI: 10.1038/emm.2016.133. View

20.

Zanger U, Schwab M . Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013; 138(1):103-41. DOI: 10.1016/j.pharmthera.2012.12.007. View