Transcellular drug transport

A. Transcellular drug transport V. DRUG ELIMINATION PHARMACOKINETICS... 

There are two principal routes of drug transport across any epithelium transcellu-lar and paracellular (Fig. 6). In the transcellular route, drugs are transported... 

Culture protocols have been published which describes an accelerated differentiation process where monolayers are ready to be used after 3-7 days of culture [90-92]. One of these systems, the so-called BD BioCoat Intestinal Epithelium Differentiation Environment, is commercially available through BD Bioscience. This system is described to produce monolayers of a quality that are comparable with the typical Caco-2 cells with respect to permeability for drugs transported transcellularly. The paracellular barrier function is however low, as indicated by high mannitol permeability and low TER. The functional capacity for active uptake and efflux is not as thoroughly characterized as for the standard Caco-2 mono-layers. 

Wielinga, P., De Waal, E., Westerhoff, H. V., Lankelma, J., In vitro transepithelial drug transport by on-line measurement cellular control of paracellular and transcellular transport,/. Pharm. Sci. 1999, 88, 1340-1347. 

There are two pathways by which a drug molecule can cross the epithelial cell the transcellular pathway, which requires the drug to permeate the cell membranes, and the paracellular pathway, in which diffusion occurs through water-filled pores of the tight junctions between the cells. Both the passive and the active transport processes may contribute to the permeability of drugs via the transcellular pathway. These transport pathways are distinctly different, and the molecular properties that influence drug transport by these routes are also different (Fig. 

Figure 8.2 Possible drug transport pathways across the intestinal mucosa, illustrating transcellular (1) and paracellular (2) modes of passive transport, transcytosis (3), carrier-mediated transport (4), and efflux transport (5). A combination of these routes often defines the overall transepithelial transport rate of nutrients and drugs.

Drug transport across corneal epithelial cells can be categorized into two major groups transcellular transport and paracellular transport... 

Figure 11.5 Vectorial transcellular transport of pravastatin, its basal-to-apical transcellular drugs in double-transfected cells, (a) The double- transport is significantly higher compared to the transfected cells expressing OATP1B1 (uptake apical-to-basal transport [177]. (b) Prediction of transporter) on the basal side and MRP2 (efflux in vivo biliary clearance of several bisubstrates of transporter) on the apical side have been rat Oatplb2 and Mrp2 from their in vitro...

Recent advances in cell and tissue culture techniques provide the potential for evaluation of drug transport or metabolism processes at the placenta. Techniques are available for culturing trophoblasts of both animal and human origin.106 However, our focus here is primarily on human systems. Primary explant and isolated cell cultures of human cytotrophoblasts have been well described 106-109 however, these systems do not form confluent monolayer systems adequate for transcellular transport studies.105... 

The most widely used ceU line in drug transport studies is the Caco-2 cell line. This is an iimnortal ceU line derived from human colon carcinoma that can be grown to monolayer on porous support. Functionally, this cell line models the colon more than the small intestine. The Caco-2 model allows characterization of both mucosal-to-serosal and serosal-to-mucosal transport and can also be used to study transcellular and paracellular transport, hi addition to expressing small intestinal brush border enzymes, Caco-2 cells also express Phase I and Phase II enzymes and can be used to evaluate metabohsm of compounds during transport across the intestinal barrier. ... 

Apart from the predominant lymphatic drug absorption mechanism, other possible mechanisms of drug transport through intestinal barriers include transcellular and paracellular absorption of drug molecules, inhibition of P-gp and/or CYP450 to accumulate the intracellular drug concentration, and production of lipoprotein/ chylomicron. 

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