Combination of a biopharmaceutic classification system and physiologically based pharmacokinetic models to predict absorption properties of baicalein in vitro and in vivo

Objective: To determine the in vitro and in vivo absorption properties of active ingredients of the Chinese medicine, baicalein, to enrich mechanistic understanding of oral drug absorption.Methods: The Biopharmaceutic Classification System(BCS) category was determined using equilibrium solubility, intrinsic dissolution rate, and intestinal permeability to evaluate intestinal absorption mechanisms of baicalein in rats in vitro. Physiologically based pharmacokinetic(PBPK) model commercial software GastroPlus~(TM) was used to predict oral absorption of baicalein in vivo.Results: Based on equilibrium solubility, intrinsic dissolution rate, and permeability values of main absorptive segments in the duodenum, jejunum, and ileum, baicalein was classified as a drug with low solubility and high permeability. Intestinal perfusion with venous sampling(IPVS) revealed that baicalein was extensively metabolized in the body, which corresponded to the low bioavailability predicted by the PBPK model. Further, the PBPK model predicted the key indicators of BCS, leading to reclassification as BCS-II. Predicted values of peak plasma concentration of the drug(C_(max)) and area under the curve(AUC)fell within two times of the error of the measured results, highlighting the superior prediction of absorption of baicalein in rats, beagles, and humans. The PBPK model supported in vitro and in vivo evidence and provided excellent prediction for this BCS class II drug.Conclusion: BCS and PBPK are complementary methods that enable comprehensive research of BCS parameters, intestinal absorption rate, metabolism, prediction of human absorption fraction and bioavailability, simulation of PK, and drug absorption in various intestinal segments across species. This combined approach may facilitate a more comprehensive and accurate analysis of the absorption characteristics of active ingredients of Chinese medicine from in vitro and in vivo perspectives.

RESEARCH ON THE ESTIMATE OF SAFETY AND TOXICITY OF P-NITROPHENOL SODIUM WITHA PHYSIOLOGICALLY BASED PHARMACOKINETICS MODEL

The safety and toxicity of chemicals given first to animals and finally to humans are generally estimated with a method of safe coefficient, which is scientifically a way lack of grounds. To make a change of the old method, we designed a Physiologically Based Pharmacokinetics Medel for the estimate of safety and toxicity of chemicais. As an example,p-nitrophenol sodium (PNP-Na) is used in the research work. Studies of the PNP-Na pharmacokinetics in bodies of rat as well as humans are made, and possibilities of making use of the Model in the estimate of safety and toxicity of chemicals are discussed.

Benchmark Dose for Dioxin Based on Gestational Diabetes Mellitus Using Coexposure Statistical Methods and an Optimized Physiologically Based Toxicokinetic Model

Dioxins are ubiquitous endocrine-disrupting substances,but determining the effects and benchmark doses in situations of coexposure is highly challenging.The objective of this study was to assess the relationship between dioxin andgestational diabetes mellitus(GDM),calculate the benchmark dose(BMD)of dioxin in coexposure scenarios,and derive a daily exposure threshold using an optimized physiologically based toxicokinetic(PBTK)model.Based on a nested casecontrol study including 77 cases with GDM and 154 controls,serum levels of 29 dioxin-like compounds(DLCs)along with 10 perfluoroalkyl acids(PFAAs),seven polybrominated diphenyl ethers(PBDEs),and five non-dioxin-like polychlorinated biphenyls(ndl-PCBs)were measured at 9−16 weeks of gestation.Bayesian machine kernel regression(BKMR)was employed to identify significant chemicals,and probit and logistic models were used to calculate BMD adjusted for significant chemicals.A physiologically based toxicokinetic(PBTK)model was optimized using polyfluorinated dibenzo-p-dioxins and dibenzofurans(PFDD/Fs)data by the Bayesian−Monte Carlo Markov chain method and was used to determine the daily dietary exposure threshold.The median serum level of total dioxin toxic equivalent(TEQ)was 7.72 pg TEQ/g fat.Logistic regression analysis revealed that individuals in the fifth quantile of total TEQ level had significantly higher odds of developing GDM compared to those in the first quantile(OR,8.87;95%CI 3.19,27.58).The BKMR analysis identified dioxin TEQ and BDE-153 as the compounds with the greatest influence.The binary logistic and probit models showed that the BMD10(benchmark dose corresponding to a 10%extra risk)and BMDL_(10)(lower bound on the BMD_(10))were 3.71 and 3.46 pg TEQ/g fat,respectively,when accounting for coexposure to BDE-153 up to the 80%level.Using the optimized PBTK model and modifying factor,it was estimated that daily exposure should be below 4.34 pg TEQ kg^(−1)bw week^(−1)in order to not reach a harmful serum concentration for GDM.Further studies should utilize coexposure statistical methods and physiologically based pharmacokinetic(PBTK)models in reference dose calculation.

Determination of the Bioaccessibility of Cadmium in Golden Thread by Physiologically Based Extraction Test Digestion Using the in vitro/Caco2 Cell Model and Subsequent Risk Assessment

Background:The ingestion of golden thread contaminated with heavy metals through the food chain leads to detrimental effects to human health.During digestion,not all of the heavy metals could be released to the gastrointestinal tract and readily to be absorbed by human body.Thus,bioaccessibility is an important issue in health risk assessments.Aims and Objectives:The aims and objectives of this study were to investigate the bioaccessibility of Cd in golden thread and assess the associated health risks based on the exposure to bioaccessible Cd.Materials and Methods:Inductively coupled plasma mass spectrometry(ICP-MS)has been applied to determine the Cd content in golden thread.Physiologically based extraction test(PBET)digestion was performed in the in vitro/Caco2 cell model to investigate the bioaccessibility of Cd in golden thread.Furthermore,the target hazard quotient(THQ)was used to assess the risks of the total and the bioaccessible content of Cd in golden thread.Results:The results revealed that the total Cd content in six batches of golden thread ranged from 3.203 to 5.723 mg/kg.After uptake by Caco2 cells,the bioaccessibility of Cd ranged from 42.36%to 59.73%.The results of the risk assessment indicated that prior to uptake by Caco2 cells,the THQ values of Cd for all batches of golden thread were greater than 1.However,after uptake by Caco2 cells,the THQ values of Cd in all samples were less than 1,thus suggesting that the risks were at a safe level.Conclusion:This study was the first to perform health risk assessment with bioaccessible heavy metals present in traditional Chinese medicine by PBET digestion using an in vitro/Caco2 cell model,thus enabling us to obtain more accurate and objective results while allowing us to avoid unnecessary government intervention and to establish more reasonable limit standards for heavy metals.

Integrated computer-aided formulation design:A case study of andrographolide/cyclodextrin ternary formulation

Current formulation development strongly relies on trial-and-error experiments in the laboratory by pharmaceutical scientists,which is time-consuming,high cost and waste materials.This research aims to integrate various computational tools,including machine learning,molecular dynamic simulation and physiologically based absorption modeling(PBAM),to enhance andrographolide(AG)/cyclodextrins(CDs)formulation design.The light GBM prediction model we built before was utilized to predict AG/CDs inclusion's binding free energy.AG/γ-CD inclusion complexes showed the strongest binding affinity,which was experimentally validated by the phase solubility study.The molecular dynamic simulation was used to investigate the inclusion mechanism between AG andγ-CD,which was experimentally characterized by DSC,FTIR and NMR techniques.PBAM was applied to simulate the in vivo behavior of the formulations,which were validated by cell and animal experiments.Cell experiments revealed that the presence of D-α-Tocopherol polyethylene glycol succinate(TPGS)significantly increased the intracellular uptake of AG in MDCKMDR1 cells and the absorptive transport of AG in MDCK-MDR1 monolayers.The relative bioavailability of the AG-CD-TPGS ternary system in rats was increased to 2.6-fold and 1.59-fold compared with crude AG and commercial dropping pills,respectively.In conclusion,this is the first time to integrate various computational tools to develop a new AG-CD-TPGS ternary formulation with significant improvement of aqueous solubility,dissolution rate and bioavailability.The integrated computational tool is a novel and robust methodology to facilitate pharmaceutical formulation design.

Bile duct ligation differently regulates protein expressions of organic cation transporters in intestine,liver and kidney of rats through activation of farnesoid X receptor by cholate and bilirubin

Body is equipped with organic cation transporters(OCTs).These OCTs mediate drug transport and are also involved in some disease process.We aimed to investigate whether liver failure alters intestinal,hepatic and renal Oct expressions using bile duct ligation(BDL)rats.Pharmacokinetic analysis demonstrates that BDL decreases plasma metformin exposure,associated with decreased intestinal absorption and increased urinary excretion.Western blot shows that BDL significantly downregulates intestinal Oct2 and hepatic Oct1 but upregulates renal and hepatic Oct2.In vitro cell experiments show that chenodeoxycholic acid(CDCA),bilirubin and farnesoid X receptor(FXR)agonist GW4064 increase OCT2/Oct2 but decrease OCT1/Oct1,which are remarkably attenuated by glycine-β-muricholic acid and silencing FXR.Significantly lowered intestinal CDCA and increased plasma bilirubin levels contribute to different Octs regulation by BDL,which are confirmed using CDCA-treated and bilirubin-treated rats.A disease-based physiologically based pharmacokinetic model characterizing intestinal,hepatic and renal Octs was successfully developed to predict metformin pharmacokinetics in rats.In conclusion,BDL remarkably downregulates expressions of intestinal Oct2 and hepatic Oct1 protein while upregulates expressions of renal and hepatic Oct2 protein in rats,finally,decreasing plasma exposure and impairing hypoglycemic effects of metformin.BDL differently regulates Oct expressions via Fxr activation by CDCA and bilirubin.

Impact of indoor ventilation efficiency on acetone inhalation exposure concentration and tissue dose in respiratory tract

A significant feature of the indoor environment is the heterogeneity of airflow and pollutant distributions,which are primarily dependent on ventilation systems.In the case of short-and high-concentration exposures to hazardous chemical pollutants,it may be necessary to precisely determine the concentration in the breathing zone or,more directly,the inhalation exposure concentration in the respiratory tract,rather than the representative room average concentration in an indoor environment,because of the non-uniformity of pollutant concentration distributions.In this study,we developed a computer-simulated person with a detailed respiratory system to predict inhalation exposure concentration and inhalation dose via transient breathing and reported a demonstrative numerical simulation for analyzing acetone concentration distributions in a simplified model room.Our numerical analysis revealed that the ventilation efficiency distribution in a room could change significantly by changing the design of the ventilation system,and that the inhalation exposure concentration estimated by a computer-simulated person could differ from the representative concentration,such as perfect-mixing or volume-averaged acetone concentration,by a factor of two or more.

An update on placental drug transport and its relevance to fetal drug exposure

Pregnant women are often complicated with diseases that require treatment with medication.Most drugs administered to pregnant women are off-label without the necessary dose,efficacy,and safety information.Knowledge concerning drug transfer across the placental barrier is essential for understanding fetal drug exposure and hence drug safety and efficacy to the fetus.Transporters expressed in the placenta,including adenosine triphosphate(ATP)-binding cassette efflux transporters and solute carrier uptake transporters,play important roles in determining drug transfer across the placental barrier,leading to fetal exposure to the drugs.In this review,we provide an update on placental drug transport,including in vitro cell/tissue,ex vivo human placenta perfusion,and in vivo animal studies that can be used to determine the expression and function of drug transporters in the placenta as well as placental drug transfer and fetal drug exposure.We also describe how the knowledge of placental drug transfer through passive diffusion or active transport can be combined with physiologically based pharmacokinetic modeling and simulation to predict systemic fetal drug exposure.Finally,we highlight knowledge gaps in studying placental drug transport and predicting fetal drug exposure and discuss future research directions to fill these gaps.