This article mainly introduces: Tandem of the human small intestine with the liver, a multi-organ microphysiological system (MPS) for more advanced human drug ADME and oral bioavailability studies
Altis Biosystems, an American in vitro model company, used CN-Bio's intestinal and hepatic dual-organ microphysiological system (Gut-Liver MPS) to simulate the physiological conditions of human oral medication, and successfully demonstrated two drugs that the current model could not adequately deplete human ADME behavior.
Traditional immortalized intestinal cell lines and suspension hepatocytes have no or very low expression levels of metabolic enzymes and are therefore unable to achieve first-pass metabolism and oral bioavailability in humans.
To improve the in vitro-to-vivo translation of drug efficacy and safety data, more human-relevant multi-organ microphysiological systems (MPS) have emerged, consisting of multiple fluidically connected organs. Here, we describe a novel MPS that uses the multi-organ system of CN-BIO to connect the jejunum (repligut planar - jejunum) to the liver, and both cells are derived from human primary cells 1.
To demonstrate its advanced capabilities, we investigated two drugs that current models do not adequately ** human ADME behavior2,3, namely temocapril (a prodrug designed to resist intestinal hydrolysis) and midazolam (midazolam, a drug known to undergo intestinal clearance).
Development of gut-liver MPS composed of primary human cells
Demonstrate the function of liver and intestinal tissues.
Provides protocols for conducting drug ADME and bioavailability studies.
In cases where the current model is unable to **human ADME behavior, the ability to improve is demonstrated with two drugs.
01- Establishment of gut-liver MPS
Figure 1A: Gut-liver MPS was established using the Physiomimix multi-organ system and dual-organ plates.
Figure 1b: For the intestinal barrier, jejunal crypt epithelial stem cells were expanded and differentiated on a biomimetic scaffold and performed under static conditions.
Figure 1 C: Liver microtissues are formed by seeding primary human hepatocytes (PHHs) on a three-dimensional collagen-coated scaffold.
02-ADME Study
Four days after phh seeding, repligut is added to the intestinal zone of the dual organ plate and fluidically connected to its corresponding liver zone (Figure 2). The ADME study begins with the addition of drugs (temocapril = 100 m, midazolam = 50 m) in the apical compartment of the intestine. After the drug is transported through the barrier, it mixes into the basolateral zone of the intestine and the liver chamber.
01- repligut exhibits distinct proliferating and differentiated cell populations with a continuous mucus layer on the apical surface (Figure 3).
02- Primary intestinal cells showed improved metabolism and transporter gene expression compared to the caco-2 cell line (Figure 4).
03-3D liver tissue is functional and metabolically active in culture-only and gut-liver co-cultures (Figure 5).
04-3D liver tissue is functionally and metabolically active in culture-only liver-only and gut-liver co-cultures (Figure 6).
05- Utilization of primary cells to improve the bioavailability of midazolam in gut-liver MPS** (Figure 7).
The gut-liver microphysiological system (gut-liver mps) simulates the physiological conditions of oral medication in humans (see Fig. 3-5). This model, which consists of primary human cells, enables more accurate studies of drug metabolism, absorption, distribution, and excretion (ADME) and bioavailability than standard in vitro models (see Figure 7).
This human-relevant enteroliver model provides an improved approach to study the pharmacokinetics of prodrugs metabolized by gastrointestinal enzymes (CES), such as Temocapril, see Figure 6.
1. c. d. edington et al., sci. reports 2018 81. 8, 1–18 (2018).
2. t. imai, m. imoto, h. sakamoto, m. hashimoto, drug metab. dispos. 33, 1185–1190 (2005).
3. c. r. jones et al., aaps j. 18, 589–604 (2016).
4. h. musther, a. olivares-morales, o. j. d. hatley,b. liu, a. r. hodjegan, eur. j. pharm.sci. 57, 280 (2014).
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