Intestinal permeability, models

Winiwarter, S., Ax, F., Lennemas, H., Hallberg, A., Pettersson, C., Karlen, A. Hydrogen bonding descriptors in the prediction of human in vivo intestinal permeability. J. Mol. Graph. Model. 2003, 21, 273-287... 

Whereas the relationship of solute permeability with lipophilicity has been studied in a large number of in vivo systems (including intestinal absorption models [54,55], blood-brain [56 58] and blood nerve [59] barrier models, and cell culture models [60 62], to name just a few), numerous in vitro model systems have been developed to overcome the complexity of working with biological membranes [63-66]. Apart from oil-water systems that are discussed here, the distribution of a solute between a water phase and liposomes is... 

Steinbaugh, MD Taylor. Comparison of intestinal permeabilities in multiple in vitro and in situ models Relationship to absorption in humans. Pharm Res 12 693-699, 1995. 

Fig. 5.2. Two-step process for evaluation of intestinal drug absorption. The first step represents the prediction of intestinal permeability (e.g., over Caco-2 monolayers) from in-silico models or from physico-chemical...

A special case in dissolution-limited bioavailability occurs when the assumption of sink condition in vivo fails that is, the drug concentration in the intestine is dose to the saturation solubility. Class IV compounds, according to BCS, are most prone to this situation due to the combination of low solubility and low permeability, although the same could also happen for class II compounds, depending primarily on the ratio between dose and solubility. Non-sink conditions in vivo lead to less than proportional increases of bioavailability for increased doses. This is illustrated in Fig. 21.8, where the fraction of drug absorbed has been simulated by use of an compartmental absorption and intestinal transit model [35] for different doses and for different permeabilities of a low-solubility, aprotic compound. 

Theory and computational aspects of intestinal permeability have been reviewed in detail by Egan and Lauri [27], Briefly, a drug must be somewhat permeable through the membrane of the intestinal tract if it is to be administered orally and achieve systemic exposure. The rate of membrane permeability is strongly related to the lipophilicity and hydrophilicity of the molecule. Thus, models with a small number of descriptors related to those two properties can provide useful predictions of drug absorption. 

The permeability of the drug substance can be determined by different approaches such as pharmacokinetic studies in humans (fraction absorbed or mass balance studies) or intestinal permeability studies (in vivo intestinal perfusion studies in humans or suitable animal models or in vitro permeation studies using excised intestinal tissue or epithelial cell culture monolayers like CaCo-2 cell line). In order to avoid misclassification of a drug subject to efflux transporters such as P-glycoprotein, functional expression of such proteins should be investigated. Low- and high-permeability model... 

Keywords Oral absorption Bioavailability Models of small intestine Intestinal permeability Intestinal perfusion techniques Intestinal versus hepatic first-pass metabolism... 

The intestinal permeability may be determined from the rate of drug appearance in mesenteric blood (i.e. dM/dt) at steady state, using Eq. 2.12. Estimating the term C[ en will again depend on the flow dynamics of the model chosen. The most commonly used experimental procedure is the single-pass perfusion (i.e. parallel tube model) and the luminal concentration can be estimated using the logarithmic mean of inlet and outlet concentrations (i.e. ). 

A more recent example of this technique has been the study on human absorption characteristics of fexofenadine [109], Fexofenadine has been shown to be a substrate for P-gp in the in vitro cell lines its disposition is altered in knockout mice lacking the gene for MDRla, and co-administration of P-gp inhibitors (e.g. ketoconazole and verapamil) was shown to increase the oral bioavailability of fexofenadine [110-113], Hence, it is suggested that the pharmacokinetics of fexofenadine appears to be determined by P-gp activity. In the human model, the intestinal permeability estimated on the basis of disappearance kinetics from the jejunal segment is low, and the fraction absorbed is estimated to be 2% [114], Co-administration of verapamil/ketoconazole did not affect the intestinal permeability estimates however, an increased extent of absorption (determined by de-convolution) was demonstrated. The increased absorption of fexofenadine was not directly related to inhibition of P-gp-mediated efflux at the apical membrane of intestinal cells as intestinal Peff was unchanged. Furthermore, the effect cannot be explained by inhibition of intestinal based metabolism, as fexofenadine is not metabolised to any major extent. It was suggested that this may reflect modulation of efflux transporters in hepatocyte cells, thereby reducing hepatobiliary extraction of fexofenadine. 

Winiwarter S, Ax F, Lennernas H, Hallberg A, Pettersson C and Karlen A (2003) Hydrogen Bonding Descriptors in the Prediction of Human In Vivo Intestinal Permeability. J Mol Graph Model 21 pp 273-287. 

Stewart BH, Chan OH, Lu RH, Reyner EL, Schmid HL, Hamilton HW, Stein-baugh BA and Taylor MD (1995) Comparison of Intestinal Permeabilities Determined in Multiple In-Vitro and In-Situ Models—Relationship to Absorption in Humans. Pharm Res 12 pp 693-699. 

Smith PL (1996) Methods for evaluating intestinal permeability and metabohsm in vitro. In Borchardt RT, Smith PL, Wilson G (eds.) Models for Assessing Drug Absorption and Metabohsm. Plenum Press, New York, pp 13-34... 

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