Drug absorption transcellular

FIG. 2 Mechanisms of drug transfer in the cellular layers that line different compartments in the body. These mechanisms regulate drug absorption, distribution, and elimination. The figure illustrates these mechanisms in the intestinal wall. (1) Passive transcellular diffusion across the lipid bilayers, (2) paracellular passive diffusion, (3) efflux by P-glycoprotein, (4) metabolism during drug absorption, (5) active transport, and (6) transcytosis [251]. 

Let us conclude this section by proposing that provided that the drug is sufficiently soluble in the gastrointestinal fluids, the complex process of intestinal drug absorption can often be satisfactorily described by focusing on passive transport across the cell membrane, and that the development of models that predict passive transcellular permeability is particularly important. Such models are the focus of the remaining part of this chapter. 

There are two routes potentially involved in drug absorption across the nasal epithelial barrier the transcellular and paracellular routes [20], Several experimental evidences dealing with the mechanism of transnasal permeation support the existence of both lipoidal pathyway (i.e., transcellular route) and an aqueous pore pathway (i.e., paracellular route). 

The successful application of in vitro models of intestinal drug absorption depends on the ability of the in vitro model to mimic the relevant characteristics of the in vivo biological barrier. Most compounds are absorbed by passive transcellular diffusion. To undergo tran-scellular transport a molecule must cross the lipid bilayer of the apical and basolateral cell membranes. In recent years, there has been a widespread acceptance of a technique, artificial membrane permeation assay (PAMPA), to estimate intestinal permeability.117118 The principle of the PAMPA is that, diffusion across a lipid layer, mimics transepithelial permeation. Experiments are conducted by applying a drug solution on top of a lipid layer covering a filter that separates top (donor) and bottom (receiver) chambers. The rate of drug appearance in the bottom wells should reflect the diffusion across the lipid layer, and by extrapolation, across the epithelial cell layer. 

Tomita, M., Shiga, M., Hayashi, M., and Awazu, S., Enhancement of colonic drug absorption by the transcellular permeation route, Pharm. Res., 5 431-435 (1988). 

Cheek, J.M., Kim, K.-J., and Crandall, E.D., NOj decreases paracellular resistance to ion and solute flow in alveolar epithelial monolayers, jcp. Lung Res., 16 561-575 (1990). Rangachari, P.K., Prior, T., and MeWade, D., Epithelial and mucosal preparations from canine eolon responses to substanee P, J. Pharmacol Exp. Ther., 254 1076-1083 (1990). Tomita, M., Hayashi, M., Toshiharu, H., and Awazu, S., Enhancement of colonic drug absorption by the transcellular permeation route, Pharm. Res., 5 786-789 (1988). 

Recent years have witnessed an explosive growth in the imderstanding of the mechanisms associated with the absorption of drugs, especially therapeutic peptides and proteins. Scientists from a variety of disciplines continue to elucidate the variables associated with the optimal formulation and delivery of drugs via the oral mucosa. A greater rmderstanding of the para- and transcellular route of drug absorption, pro-... 

Transcellular Drug Absorption—Simple and Facilitated Diffusion... 

Transcellular Drug Absorption—Nondiffusional Processes 1.5.5.1 Carrier-Mediated Approaches to Drug Absorption... 

The pathways of drug absorption are transcellular and paracellular. Moreover, absorption can be due to the vesicular- or receptor-mediated transport or it can occur through the aqueous pores on the mucosa surface. 

Abstract This chapter attempts to give an overview on the properties of the intestinal epithelium with regard to both, barriers to transcellular (transporter and efflux systems) and paracellular (tight junctional complex) drug absorption and transport systems and tight junction modulation. A short introduction into the relation between the innate immune system and modulation of paracellular permeability is equally given. 

Swenson ES, Milisen WB, Curatolo W (1994) Intestinal permeability enhancement structure-activity and structure-toxicity relationships for nonylphenoxypolyoxyethylene surfactant permeability enhancers. Pharm Res 11 1501-1504 Tomita M, Hayashi M, Horie T, Ishizawa T, Awazu S (1988) Enhancement of colonic drug absorption by the transcellular permeation route. Pharm Res 5 786-789 Tomita M, Sawada T, Ogawa T, Ouchi H, Hayashi M, Awazu S (1992) Differences in the enhancing effects of sodium caprate on colonic and jejunal drug absorption. Pharm Res 9 648-653... 

The PAMPA model is a simple model for fast determination of transcellular in vivo drug absorption. Coating a hydropho-... 

The rate of drug absorption for the transcellular route is pH-dependent. Such dependency results from the fact that the membrane/aqueous partition coefficient for an ionizable drug is pH-dependent. 

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