Publications

@article{hudson_comparing_2025,

title = {Comparing the Altis RepliGut Organoid System to MDCK Monolayers in Predicting the Oral Absorption of Lenalidomide},

author = {Cole S. Hudson and Jonathan Cheong and Jesse Yu and Eugene C. Chen and Laurent Salphati and Matthew R. Durk and Benjamin Lai and Karen Samy},

url = {https://www.mdpi.com/1999-4923/17/9/1140},

doi = {10.3390/pharmaceutics17091140},

issn = {1999-4923},

year  = {2025},

date = {2025-08-30},

journal = {Pharmaceutics},

volume = {17},

number = {9},

pages = {1140},

abstract = {Background: Predicting oral drug absorption in humans is critical during early drug development. Current in vitro systems to predict absorption (e.g., PAMPA and MDCK cells) are lacking for certain classes of drugs. Intestinal organoids are emerging as a promising alternative that offers several potential advantages. In this study, we utilized human intestinal organoid-derived monolayers to predict oral absorption of lenalidomide. Methods: Human jejunal organoids (RepliGut®) were cultured as monolayers on transwell plates and differentiated into intestinal epithelial cells. Lenalidomide permeability in the organoid system was compared with the permeability in the conventional Madin-Darby Canine Kidney cell (MDCK) monolayer system, as well as P-gp knockout, human P-gp overexpressing, and human BCRP overexpressing MDCK cells across a concentration range of 1 to 500 µM. Male Sprague Dawley rats were administered lenalidomide orally/intravenously, and concentrations in the serum, urine, and feces were measured and modeled in Phoenix WinNonlin. Results: Orally administered lenalidomide was well absorbed by rats at all doses (bioavailability = 68–120%). In the human jejunal organoid model, lenalidomide apparent permeability (Papp) was approximately 0.6 × 10−6 cm/s independent of the concentration used (1–500 µM). In contrast, lenalidomide Papp was significantly lower in gMDCK cell monolayers, approximately 0.2 × 10−6 cm/s. Additionally, lenalidomide was identified as a P-gp/BCRP substrate in intestinal organoids and gMDCK P-gp and BCRP overexpressing cells. Conclusions: Lenalidomide Papp was significantly lower in gMDCK monolayers than expected based on its high bioavailability. Our results suggest that organoid systems can better capture transporter and paracellularly mediated effects on drug permeability, which may allow for more accurate predictions of in vivo absorption.},

note = {Publisher: Multidisciplinary Digital Publishing Institute},

keywords = {{MDCK} cells, drug permeability, intestinal organoids, lenalidomide, oral bioavailability},

pubstate = {published},

tppubtype = {article}

}

@article{sharma_developing_2024,

title = {Developing an adult stem cell derived microphysiological intestinal system for predicting oral prodrug bioconversion and permeability in humans},

author = {Abhinav Sharma and Liang Jin and Xue Wang and Yue-Ting Wang and David M. Stresser},

url = {https://pubs.rsc.org/en/content/articlelanding/2024/lc/d3lc00843f},

doi = {10.1039/D3LC00843F},

issn = {1473-0189},

year  = {2024},

date = {2024-01-17},

urldate = {2024-01-17},

journal = {Lab Chip},

volume = {24},

number = {2},

pages = {339–355},

abstract = {Microphysiological systems (MPS) incorporating human intestinal organoids have shown the potential to faithfully model intestinal biology with the promise to accelerate development of oral prodrugs. We hypothesized that an MPS model incorporating flow, shear stress, and vasculature could provide more reliable measures of prodrug bioconversion and permeability. Following construction of jejunal and duodenal organoid MPS derived from 3 donors, we determined the area under the concentration–time (AUC) curve for the active drug in the vascular channel and characterized the enzymology of prodrug bioconversion. Fosamprenavir underwent phosphatase mediated hydrolysis to amprenavir while dabigatran etexilate (DABE) exhibited proper CES2- and, as anticipated, not CES1-mediated de-esterification, followed by permeation of amprenavir to the vascular channel. When experiments were conducted in the presence of bio-converting enzyme inhibitors (orthovanadate for alkaline phosphatase; bis(p-nitrophenyl)phosphate for carboxylesterase), the AUC of the active drug decreased accordingly in the vascular channel. In addition to functional analysis, the MPS was characterized through imaging and proteomic analysis. Imaging revealed proper expression and localization of epithelial, endothelial, tight junction and catalytic enzyme markers. Global proteomic analysis was used to analyze the MPS model and 3 comparator sources: an organoid-based transwell model (which was also evaluated for function), Matrigel embedded organoids and finally jejunal and duodenal cadaver tissues collected from 3 donors. Hierarchical clustering analysis (HCA) and principal component analysis (PCA) of global proteomic data demonstrated that all organoid-based models exhibited strong similarity and were distinct from tissues. Intestinal organoids in the MPS model exhibited strong similarity to human tissue for key epithelial markers via HCA. Quantitative proteomic analysis showed higher expression of key prodrug converting and drug metabolizing enzymes in MPS-derived organoids compared to tissues, organoids in Matrigel, and organoids on transwells. When comparing organoids from MPS and transwells, expression of intestinal alkaline phosphatase (ALPI), carboxylesterase (CES)2, cytochrome P450 3A4 (CYP3A4) and sucrase isomaltase (SI) was 2.97-, 1.2-, 11.3-, and 27.7-fold higher for duodenum and 7.7-, 4.6-, 18.1-, and 112.2-fold higher for jejunum organoids in MPS, respectively. The MPS approach can provide a more physiological system than enzymes, organoids, and organoids on transwells for pharmacokinetic analysis of prodrugs that account for 10% of all commercial medicines.},

note = {Publisher: The Royal Society of Chemistry},

keywords = {absorption, Bioavailability, Biological Transport, Caco-2 Cells, drug absorption, drug metabolising enzymes ({DME}), drug permeability, intestinal barrier, oral bioavailability, permeability},

pubstate = {published},

tppubtype = {article}

}