Development and application of a physiologically based pharmacokinetic model for entrectinib in rats and scale-up to humans: Route-dependent gut wall metabolism

Seo, Seong-Wook; Han, Dong-Gyun; Choi, Eun Young; Park, Taeuk; Byun, Jong Hyuk; Cho, Hyun‐Jong; Jung, Il Hyo; Yoon, In‐Soo

doi:10.1016/j.biopha.2021.112520

Cited by 12 publications

(6 citation statements)

References 45 publications

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“…Unlike humans, digoxin is also metabolized by Cyp3a2 in rodents, so a model was constructed by considering the inter-tissue proteomics and kinetics data of both P-gp and Cyp3a2. The existing rat PBPK models generally use overall clearance or rate constant data to predict the observed systemic or tissue drug concentrations; however, such models are not fully mechanistic as they do not consider tissue abundance of DMET proteins. ,− Therefore, the animal PBPK modeling could be further improved by the integration of tissue DMET abundance data provided in this study. In particular, tissue DMET abundance has a potential to predict tissue drug concentration (relative expression factor-based in vitro to in vivo extrapolation), which is critical for interpreting tissue-specific toxicity data .…”

Section: Discussionmentioning

confidence: 99%

Quantitative Characterization of Clinically Relevant Drug-Metabolizing Enzymes and Transporters in Rat Liver and Intestinal Segments for Applications in PBPK Modeling

et al. 2023

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Rats are extensively used as a preclinical model for assessing drug pharmacokinetics (PK) and tissue distribution; however, successful translation of the rat data requires information on the differences in drug metabolism and transport mechanisms between rats and humans. To partly fill this knowledge gap, we quantified clinically relevant drug-metabolizing enzymes and transporters (DMETs) in the liver and different intestinal segments of Sprague-Dawley rats. The levels of DMET proteins in rats were quantified using the global proteomics-based total protein approach (TPA) and targeted proteomics. The abundance of the major DMET proteins was largely comparable using quantitative global and targeted proteomics. However, global proteomics-based TPA was able to detect and quantify a comprehensive list of 66 DMET proteins in the liver and 37 DMET proteins in the intestinal segments of SD rats without the need for peptide standards. Cytochrome P450 (Cyp) and UDP-glycosyltransferase (Ugt) enzymes were mainly detected in the liver with the abundance ranging from 8 to 6502 and 74 to 2558 pmol/g tissue. P-gp abundance was higher in the intestine (124.1 pmol/g) as compared to that in the liver (26.6 pmol/g) using the targeted analysis. Breast cancer resistance protein (Bcrp) was most abundant in the intestinal segments, whereas organic anion transporting polypeptides (Oatp) 1a1, 1a4, 1b2, and 2a1 and multidrug resistance proteins (Mrp) 2 and 6 were predominantly detected in the liver. To demonstrate the utility of these data, we modeled digoxin PK by integrating protein abundance of P-gp and Cyp3a2 into a physiologically based PK (PBPK) model constructed using PK-Sim software. The model was able to reliably predict the systemic as well as tissue concentrations of digoxin in rats. These findings suggest that proteomics-informed PBPK models in preclinical species can allow mechanistic PK predictions in animal models including tissue drug concentrations.

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Section: Discussionmentioning

confidence: 99%

Quantitative Characterization of Clinically Relevant Drug-Metabolizing Enzymes and Transporters in Rat Liver and Intestinal Segments for Applications in PBPK Modeling

et al. 2023

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“… 2011 ; Seo et al. 2022 ). For intravenous administration, zeaxanthin (5 mg/kg) was infused over 30 min into the femoral vein, and simultaneously, the same volume of vehicle solution consisting of dimethyl sulfoxide, ethanol, and polyethylene glycol 400 (20:5:75, v/v/v) was infused over 30 min into the portal vein (infusion pump: LEGATO ® 101 syringe pump, KD Scientific Inc., MA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…The linearity, sensitivity, selectivity, precision, accuracy, extraction recovery, and matrix effects of the method were assessed as previously described (Seo et al. 2021 , 2022 ). Analytical stability was determined under various handling and storage conditions, such as benchtop, freeze‑thaw, post‑preparative, and long‑term storage, at two different QC levels (LQC and HQC).…”

Section: Methodsmentioning

confidence: 99%

Factors determining the oral absorption and systemic disposition of zeaxanthin in rats: in vitro , in situ , and in vivo evaluations

Seo

Han

Choi

et al. 2022

Pharmaceutical Biology

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Context Zeaxanthin is a yellow‑coloured dietary carotenoid widely recognized as an essential component of the macula. It exerts blue light filtering and antioxidant activities, offering eye health and vision benefits. Objective This study explores the oral absorption and systemic disposition of zeaxanthin from biopharmaceutical and pharmacokinetic perspectives. Materials and methods In vivo intravenous (5 and 10 mg/kg) and intraportal (5 mg/kg) pharmacokinetic studies were performed to determine intrinsic tissue‑blood partition coefficient, elimination pathway, and hepatic clearance, of zeaxanthin in rats. Moreover, in vitro physicochemical property test, in situ closed loop study, in vivo oral pharmacokinetic study (20 and 100 mg/kg), and in vivo lymphatic absorption study (100 mg/kg) were conducted to investigate the gut absorption properties of zeaxanthin and assess the effects of several lipids on the lymphatic absorption of zeaxanthin in rats. Results Zeaxanthin exhibited poor solubility (≤144 ng/mL) and stability (6.0–76.9% of the initial amount remained at 24 h) in simulated gut luminal fluids. Gut absorption of zeaxanthin occurred primarily in the duodenum, but the major fraction (≥84.7%) of the dose remained unabsorbed across the entire gut tract. Considerable fractions of intravenous zeaxanthin accumulated in the liver, lung, and spleen (21.3, 11.7, and 2.0%, respectively). It was found that the liver is the major eliminating organ of zeaxanthin, accounting for 53.5–90.1% of the total clearance process (hepatic extraction ratio of 0.623). Discussion and conclusions To our knowledge, this is the first systematic study to report factors that determine the oral bioavailability and systemic clearance of zeaxanthin.

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“…At predetermined time points (0, 15, 30, 60, 120, 240, 480, and 1440 min), 120 μL of the samples were collected, diluted with acetonitrile to obtain an appropriate final concentration, and analyzed using the LC‐MS/MS method. In vitro protein binding and blood distribution studies were conducted as previously described (Han et al, 2020; Seo et al, 2022). Further details are provided in the Supporting Information.…”

Section: Methodsmentioning

confidence: 99%

Investigation of the factors responsible for the low oral bioavailability of alizarin using a sensitive LC‐MS/MS method: In vitro, in situ, and in vivo evaluations

Seo

Han

Baek

et al. 2023

Drug Development Research

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Alizarin (1,2-dihydroxyanthraquinone) is an anthraquinone reddish dye widely used for painting and textile dyeing. As the biological activity of alizarin has recently attracted increasing attention from researchers, its therapeutic potential as complementary and alternative medicine is of interest. However, no systematic research has been conducted on the biopharmaceutical and pharmacokinetic aspects of alizarin. Therefore, this study aimed to comprehensively investigate the oral absorption and intestinal/hepatic metabolism of alizarin using a simple and sensitive tandem mass spectrometry method developed and validated in-house. The present method for the bioanalysis of alizarin has merits, including a simple pretreatment procedure, small sample volume, and adequate sensitivity. Alizarin exhibited pHdependent moderate lipophilicity and low solubility with limited intestinal luminal stability. Based on the in vivo pharmacokinetic data, the hepatic extraction ratio of alizarin was estimated to be 0.165-0.264, classified as a low level of hepatic extraction. In an in situ loop study, considerable fractions (28.2%-56.4%) of the alizarin dose were significantly absorbed in gut segments from the duodenum to ileum, suggesting that alizarin may be classified as the Biopharmaceutical Classification System class II. An in vitro metabolism study using rat and human hepatic S9 fractions revealed that glucuronidation and sulfation, but not NADPHmediated phase I reactions and methylation, are significantly involved in the hepatic metabolism of alizarin. Taken together, it can be estimated that the fractions of oral alizarin dose unabsorbed from the gut lumen and eliminated by the gut and liver before reaching the systemic circulation are 43.6%-76.7%, 0.474%-36.3%, and 3.77%-5.31% of the dose, respectively, resulting in a low oral bioavailability of 16.8%. Therefore, the oral bioavailability of alizarin depends primarily on its chemical degradation in the gut lumen and secondarily on first-pass metabolism.

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Development and application of a physiologically based pharmacokinetic model for entrectinib in rats and scale-up to humans: Route-dependent gut wall metabolism

Cited by 12 publications

References 45 publications

Quantitative Characterization of Clinically Relevant Drug-Metabolizing Enzymes and Transporters in Rat Liver and Intestinal Segments for Applications in PBPK Modeling

Quantitative Characterization of Clinically Relevant Drug-Metabolizing Enzymes and Transporters in Rat Liver and Intestinal Segments for Applications in PBPK Modeling

Factors determining the oral absorption and systemic disposition of zeaxanthin in rats: in vitro , in situ , and in vivo evaluations

Investigation of the factors responsible for the low oral bioavailability of alizarin using a sensitive LC‐MS/MS method: In vitro, in situ, and in vivo evaluations

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