Vitro Cell Models

Furthermore, the Pefr data can be integrated with solubility/dissolution data to predict the oral absorption from the solid dosage form (see Chapter 10). Gastrointestinal transit absorption model (GITA) [12, 13], advanced compartmental absorption and transit model (ACAT, GastroPlus), advanced drug absorption and metabolism model (ADAM, SimCYP) and so on have been reported as useful integration models (see Chapter 10). 

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An in vitro cell model resembles the remodeling process of osteoclastic bone resorption followed by osteoblastic bone formation investigate the influence of lead on the communication between these cells determine if lead in the medium (i.e. extracellular fluid) or in the matrix (i.e. in the bone) has different effects on osteoclasts and osteoblasts... 

Schmidt MC, Peter H, Lang SR, Ditzinger G, Merkle HP (1998) In vitro cell models to study nasal mucosal permeability and metabolism. Adv Drug Del Rev 29 51-79. 

To meet the need of conducting HTS for ADME-Tox properties, many slow and expensive in vivo ADME assays are now being replaced by in vitro cell models. For intestinal absorption, Caco-2 cell lines and Madin Darby canine kidney (MDCK) cell lines are widely used to predict the absorption rate of candidate drug compounds across the intestinal epithelial cell barrier. A number of models for Caco-2 cell permeability and MDCK cell permeability have been reported that predict the oral absorption properties of drugs, mostly limited to small organic molecules. Caco-2 and MDCK permeability are related to "A" and "D" in the ADME-Tox. 

Figure 6.3). Metoprolol permeability is often regarded as a borderline between high and low permeability and is used as a standard compound for in vitro cell models. 

Garberg et al. compared a number of in vitro cell models of the BBB with in vivo data (including primary cow and human brain endothelial cells co-cultured with astrocytes, MDCK, MDCK-MDRl, Caco-2, ECV304/C6, MBEC4, SV-ARBEC cocultured with astrocytes). The best correlation, although poor, was seen with cow brain endothelial cells (r 0.43) and MDCK (r 0.46). The correlation was improved with Caco-2 when only passively transported compounds were included in the analysis (r = 0.86), BBEC showing a similar correlation [39]. 

The carboxylate metabolite of tasidotin was also studied using in-vitro cell models which showed the metabolite to have pharmacologic activity 10- to 30-fold less potent than the parent tasidotin (IC50 values ranged from 1(T7 M to 10 6 M). When the metabolite was studied in vivo using an MX-1 (breast cancer) xenograft model in mice, the metabolite showed no activity. 

Silva JM, Morin PE, Day SH, et al. Refinement of an in vitro cell model for cytochrome P450 induction. Drug Metab Dispos 1998 26 490-496. 

In addition to in vitro cell models, opioid agonists could induce the rapid endocytosis of the receptor in organo cultures or primary neuronal cultures, and also neurons in vivo. Treatment of longitudinal muscle-myenteric plexus preparation or the primary hippocampal neuron cultures with DAMGO resulted in internalization of the mu opioid receptor [146,147]. Similar observation was obtained with fluorescently labeled opioid peptides Fluo-dermorphin and Fluo-deltorphin [148]. Within 15 min of an intra-peritoneal injection of etorphine, mu opioid receptor immunoreactivity was observed in the endosomal structures of the myenteric neurons of guinea pig ileum [149]. Again, rapid clustering of a spliced variant of mu opioid receptor MOR-1C was observed in the lateral septum of the mouse after intracere-... 

O Leary, K.A., Day, A.J., Needs, RW., O Brien, N.M., and Williamson, G., Metabolism of quercetin glucuronides in an in vitro cell model, in Biologically-Active Phytochemicals in Foods Analysis, Metabolism, Bioavailability and Function, W. Pfannhauser, G.R. Fenwick, and S. Khokhar, Eds., Royal Society of Chemistry, Cambridge, U.K., pp. 441 142, 2001. 

Lundquist S, Renftel M, Brillault J, Fenart L, Cecchelli R, Dehouck MP (2002) Prediction of drug transport through the blood-brain barrier in vivo a comparison between two in vitro cell models. Pharm Res 19(7) 976-981... 

When cell biologists developed ways to propagate animal cells in culture, animal vimses could be studied at the molecular level. The most widely used in vitro cell models are those derived from immortalized differentiated cell types called cell lines. Immortalized cell lines are often established from tumors, usually from mouse or human tumors. Today, there are over 5000 animal cell lines available for animal cell studies. Table 30.1 lists several of the more commonly used animal cell lines. 

Yin L, Ding J, He C, Cui L, Tang C, et aL Dmg permeability and mucoadhesion properties of thio-lated trimethyl chitosan nanopaiticles in oral insulin delivery. Biomaterials. 2009 30 5691-700. Antunes F, Andrade F, Araujo F, Ferreira D, Sarmento B. Establishment of a triple co-culture in vitro cell models to study intestinal absorption of peptide dmgs. Eur J Pharm Biopharm. 2013 83 427-35. 

Plat et al (2000) recently showed that 2.5 g/day of plant stanols as fatty acid esters consumed with a meal in one daily dose was as effective at reducing serum total and LDL cholesterol levels as the same amount divided into three doses taken throughout the day (Figure 8). This indicates that additional mechanisms at the absorptive sites of the enterocytes or within the enterocytes must play a role in the overall effect of plant sterols on cholesterol absorption. In an in vitro cell model. Field et al (1997) showed that sitosterol was taken up by Caco-2 cells less efficiently than cholesterol. Furthermore, plant sterols and stanols are absorbed into the cell walls of the digestive tract in animals (Bhattacharyya and Lopez, 1979 Sanders et al, 2000). 

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