An Agent-Based Approach to Dynamically Represent the Pharmacokinetic Properties of Baicalein
Tóm tắt
Baicalein, a typical flavonoid presented in Scutellariae radix, exhibits a unique metabolic profile during first-pass metabolism: parallel glucuronidation and sulfation pathways, with possible substrate inhibition in both pathways. In this project, we aimed to construct an agent-based model to dynamically represent baicalein pharmacokinetics and to verify the substrate inhibition hypothesis. The model consisted of three 3D spaces and two membranes: apical space (S1), intracellular space (S2), basolateral space (S3), apical membrane (M1), and basolateral membrane (M2). In silico enzymes (UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs)) and binder components were placed in S2. The model was then executed to simulate one-pass metabolism experiments of baicalein. With the implementation of a two-site enzyme design, the simulated results captured the preset qualitative and quantitative features of the wet-lab observations. The feasible parameter set showed that substrate inhibition happened in both conjugation pathways of baicalein. The simulation results suggested that the sulfation pathway was dominant at low concentrations and that SULT was more inclined to substrate inhibition than UGT. Cross-model validation was satisfactory. Our findings were consistent with a previously reported catenary model. We conclude that the mechanisms represented by our model are plausible. Our novel modeling approach could dynamically represent the metabolic pathways of baicalein in a Caco-2 system.
Tài liệu tham khảo
citation_journal_title=Zhong Yao Cai; citation_title=Study on the inhibitory activity, in vitro, of baicalein and baicalin against skin fungi and bacteria; citation_author=D Yang, H Hu, S Huang, JP Chaumont, J Millet; citation_volume=23; citation_issue=5; citation_publication_date=2000; citation_pages=272-4; citation_id=CR1
citation_journal_title=Planta Med; citation_title=Evaluation of the anti-inflammatory effect of baicalein on dextran sulfate sodium-induced colitis in mice; citation_author=T Hong, GB Jin, S Cho, JC Cyong; citation_volume=68; citation_issue=3; citation_publication_date=2002; citation_pages=268-71; citation_doi=10.1055/s-2002-23143; citation_id=CR2
citation_journal_title=Am J Physiol Heart Circ Physiol; citation_title=Baicalein attenuates oxidant stress in cardiomyocytes; citation_author=ZH Shao, TL Vanden Hoek, Y Qin, LB Becker, PT Schumacker, CQ Li; citation_volume=282; citation_issue=3; citation_publication_date=2002; citation_pages=H999-1006; citation_doi=10.1152/ajpheart.00163.2001; citation_id=CR3
citation_journal_title=J Biochem; citation_title=Mechanisms of inhibition of various cellular DNA and RNA polymerases by several flavonoids; citation_author=K Ono, H Nakane; citation_volume=108; citation_issue=4; citation_publication_date=1990; citation_pages=609-13; citation_id=CR4
citation_journal_title=Clin Exp Allergy; citation_title=Effects of luteolin, quercetin and baicalein on immunoglobulin E-mediated mediator release from human cultured mast cells; citation_author=M Kimata, M Shichijo, T Miura, I Serizawa, N Inagaki, H Nagai; citation_volume=30; citation_issue=4; citation_publication_date=2000; citation_pages=501-8; citation_doi=10.1046/j.1365-2222.2000.00768.x; citation_id=CR5
citation_journal_title=Pharm Res; citation_title=Role of intestinal first-pass metabolism of baicalein in its absorption process; citation_author=L Zhang, G Lin, Q Chang, Z Zuo; citation_volume=22; citation_issue=7; citation_publication_date=2005; citation_pages=1050-8; citation_doi=10.1007/s11095-005-5303-7; citation_id=CR6
citation_journal_title=Pharm Res; citation_title=Involvement of UDP-glucuronosyltransferases in the extensive liver and intestinal first-pass metabolism of flavonoid baicalein; citation_author=L Zhang, G Lin, Z Zuo; citation_volume=24; citation_issue=1; citation_publication_date=2007; citation_pages=81-9; citation_doi=10.1007/s11095-006-9126-y; citation_id=CR7
citation_journal_title=Eur J Pharm Sci; citation_title=Mechanistic study on the intestinal absorption and disposition of baicalein; citation_author=L Zhang, G Lin, B Kovacs, M Jani, P Krajcsi, Z Zuo; citation_volume=31; citation_issue=3-4; citation_publication_date=2007; citation_pages=221-31; citation_doi=10.1016/j.ejps.2007.04.001; citation_id=CR8
citation_journal_title=J Pharmacol Exp Ther; citation_title=A catenary model to study transport and conjugation of baicalein, a bioactive flavonoid, in the Caco-2 cell monolayer: demonstration of substrate inhibition; citation_author=H Sun, L Zhang, EC Chow, G Lin, Z Zuo, KS Pang; citation_volume=326; citation_issue=1; citation_publication_date=2008; citation_pages=117-26; citation_doi=10.1124/jpet.108.137463; citation_id=CR9
citation_journal_title=Pharm Res; citation_title=At the biological modeling and simulation frontier; citation_author=CA Hunt, GE Ropella, TN Lam, J Tang, SH Kim, JA Engelberg; citation_volume=26; citation_issue=11; citation_publication_date=2009; citation_pages=2369-400; citation_doi=10.1007/s11095-009-9958-3; citation_id=CR10
citation_journal_title=J Pharmacol Exp Ther; citation_title=Mechanistic insight from in silico pharmacokinetic experiments: roles of P-glycoprotein, Cyp3A4 enzymes, and microenvironments; citation_author=TN Lam, CA Hunt; citation_volume=332; citation_issue=2; citation_publication_date=2010; citation_pages=398-412; citation_doi=10.1124/jpet.109.160739; citation_id=CR11
citation_journal_title=Drug Metab Dispos; citation_title=Discovering plausible mechanistic details of hepatic drug interactions; citation_author=TN Lam, CA Hunt; citation_volume=37; citation_issue=1; citation_publication_date=2009; citation_pages=237-46; citation_doi=10.1124/dmd.108.023820; citation_id=CR12
citation_journal_title=Drug Dev Res; citation_title=Moving beyond in silico tools to in silico science in support of drug development research; citation_author=CA Hunt, GEP Ropella; citation_volume=72; citation_issue=2; citation_publication_date=2011; citation_pages=153-61; citation_doi=10.1002/ddr.20412; citation_id=CR13
citation_journal_title=CPT: Pharm Syst Pharmacol; citation_title=Agent-based modeling in systems pharmacology; citation_author=J Cosgrove, J Butler, K Alden, M Read, V Kumar, L Cucurull-Sanchez; citation_volume=4; citation_issue=11; citation_publication_date=2015; citation_pages=615-29; citation_id=CR14
citation_journal_title=Theor Biol Med Model; citation_title=Relational grounding facilitates development of scientifically useful multiscale models; citation_author=CA Hunt, GE Ropella, TN Lam, AD Gewitz; citation_volume=8; citation_publication_date=2011; citation_pages=35; citation_doi=10.1186/1742-4682-8-35; citation_id=CR15
citation_journal_title=Int J Pharm; citation_title=Investigation of intestinal absorption and disposition of green tea catechins by Caco-2 monolayer model; citation_author=L Zhang, Y Zheng, MS Chow, Z Zuo; citation_volume=287; citation_issue=1-2; citation_publication_date=2004; citation_pages=1-12; citation_doi=10.1016/j.ijpharm.2004.08.020; citation_id=CR16
citation_journal_title=Science; citation_title=Pattern-oriented modeling of agent-based complex systems: lessons from ecology; citation_author=V Grimm, E Revilla, U Berger, F Jeltsch, WM Mooij, SF Railsback; citation_volume=310; citation_issue=5750; citation_publication_date=2005; citation_pages=987-91; citation_doi=10.1126/science.1116681; citation_id=CR17
citation_journal_title=Pharm Res; citation_title=An in silico transwell device for the study of drug transport and drug-drug interactions; citation_author=LX Garmire, DG Garmire, CA Hunt; citation_volume=24; citation_issue=12; citation_publication_date=2007; citation_pages=2171-86; citation_doi=10.1007/s11095-007-9391-4; citation_id=CR18
citation_journal_title=Conf Proc IEEE Eng Med Biol Soc; citation_title=Mechanistic simulations explain paradoxical saquinavir metabolism during in vitro vectorial transport study; citation_author=TN Lam, CA Hunt; citation_volume=2008; citation_publication_date=2008; citation_pages=5462-5; citation_id=CR19
citation_journal_title=Pharm Res; citation_title=Mechanistic study of the cellular interplay of transport and metabolism using the synthetic modeling method; citation_author=Y Liu, CA Hunt; citation_volume=23; citation_issue=3; citation_publication_date=2006; citation_pages=493-505; citation_doi=10.1007/s11095-006-9505-4; citation_id=CR20
citation_journal_title=Biosystems; citation_title=Studies of intestinal drug transport using an in silico epithelio-mimetic device; citation_author=Y Liu, CA Hunt; citation_volume=82; citation_issue=2; citation_publication_date=2005; citation_pages=154-67; citation_doi=10.1016/j.biosystems.2005.06.008; citation_id=CR21
Spector P. Data manipulation with R. 2008.
Wickham H. ggplot2: elegant graphics for data analysis: Springer; 2009.
citation_journal_title=Drug Metab Dispos; citation_title=Permeability, transport, and metabolism of solutes in Caco-2 cell monolayers: a theoretical study; citation_author=H Sun, KS Pang; citation_volume=36; citation_issue=1; citation_publication_date=2008; citation_pages=102-23; citation_doi=10.1124/dmd.107.015321; citation_id=CR24
citation_journal_title=J Pharm Biomed Anal; citation_title=Rapid resolution liquid chromatography (RRLC) analysis and studies on the stability of Shuang-Huang-Lian preparations; citation_author=Y-C Ma, X-Q Wang, F Hou, J Ma, M Luo, A Chen; citation_volume=54; citation_issue=2; citation_publication_date=2011; citation_pages=265-72; citation_doi=10.1016/j.jpba.2010.08.019; citation_id=CR25
citation_journal_title=AAPS J; citation_title=Comparison of intestinal absorption and disposition of structurally similar bioactive flavones in Radix Scutellariae; citation_author=C Li, L Zhang, L Zhou, SK Wo, G Lin, Z Zuo; citation_volume=14; citation_issue=1; citation_publication_date=2012; citation_pages=23-34; citation_doi=10.1208/s12248-011-9310-9; citation_id=CR26
citation_journal_title=Pharmazie; citation_title=Biotransformation of baicalin to baicalein significantly strengthens the inhibition potential towards UDP-glucuronosyltransferases (UGTs) isoforms; citation_author=Y Teng, H Nian, H Zhao, P Chen, G Wang; citation_volume=68; citation_issue=9; citation_publication_date=2013; citation_pages=763-7; citation_id=CR27
citation_journal_title=J Biol Chem; citation_title=Structure of a human carcinogen-converting enzyme, SULT1A1. Structural and kinetic implications of substrate inhibition; citation_author=NU Gamage, RG Duggleby, AC Barnett, M Tresillian, CF Latham, NE Liyou; citation_volume=278; citation_issue=9; citation_publication_date=2003; citation_pages=7655-62; citation_doi=10.1074/jbc.M207246200; citation_id=CR28
citation_journal_title=J Biol Chem; citation_title=Sulfuryl transfer: the catalytic mechanism of human estrogen sulfotransferase; citation_author=H Zhang, O Varlamova, FM Vargas, CN Falany, TS Leyh; citation_volume=273; citation_issue=18; citation_publication_date=1998; citation_pages=10888-92; citation_doi=10.1074/jbc.273.18.10888; citation_id=CR29
citation_journal_title=Mol Pharmacol; citation_title=Expression and characterization of a novel thyroid hormone-sulfating form of cytosolic sulfotransferase from human liver; citation_author=J Wang, JL Falany, CN Falany; citation_volume=53; citation_issue=2; citation_publication_date=1998; citation_pages=274-82; citation_id=CR30
citation_journal_title=Wiley Interdiscip Rev Syst Biol Med; citation_title=Agent-based models in translational systems biology; citation_author=G An, Q Mi, J Dutta-Moscato, Y Vodovotz; citation_volume=1; citation_issue=2; citation_publication_date=2009; citation_pages=159-71; citation_doi=10.1002/wsbm.45; citation_id=CR31
citation_journal_title=Wound Repair Regen; citation_title=Translational systems biology using an agent-based approach for dynamic knowledge representation: an evolutionary paradigm for biomedical research; citation_author=GC An; citation_volume=18; citation_issue=1; citation_publication_date=2010; citation_pages=8-12; citation_doi=10.1111/j.1524-475X.2009.00568.x; citation_id=CR32