title: An Agent-Based Approach to Dynamically Represent the Pharmacokinetic Properties of Baicalein.
abstract: 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.
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhu
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
authors.forename: Jianyuan
authors.initials: J
authors.lastname: Deng
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zuo
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong. teddylam@cuhk.edu.hk.
authors.forename: Tai Ning
authors.identifier: 0000-0002-7259-4050
authors.initials: TN
authors.lastname: Lam
mesh_terms: D000975:Antioxidants / Q000493:pharmacokinetics*; D018938:Caco-2 Cells; D044950:Flavanones / Q000493:pharmacokinetics*; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D008962:Models, Theoretical; D015238:Sulfotransferases / Q000378:metabolism
chemical_list: D000975:Antioxidants; D044950:Flavanones; C006680:baicalein; D014453:Glucuronosyltransferase; D015238:Sulfotransferases
keywords: agent-based; baicalein; enzyme; modeling and simulation; pharmacokinetic