Prediction of the fraction of dose absorbed from the intestine (Fa) in man is essential in the early drug discovery stage. In-vitro assays in Caco-2 and MDCK cells are routinely used for that purpose, and their predictive value has been reported. However, in-situ techniques might provide a more accurate estimation of Fa. In this study, we evaluated a single-pass intestinal-perfusion (SPIP) method in the rat for its use in the prediction of absorption in man and compared it with a previous report using cell-based assays. Effective permeability coefficients (Peff) were determined in rats for 14 compounds, and ranged from 0.043x 10(-4) cm s(-1) to 1.67 x 10(-4) cm s(-1). These values strongly correlated (r2 = 0.88) with reported Peff values for man. In addition, the Spearman rank correlation coefficient calculated for in-situ-derived Peff and absorption in man was 0.92 while for the previously tested in-vitro Caco-2 and MDCK systems vs absorption in man, the correlation coefficients were 0.61 and 0.59, respectively. SPIP provided a better prediction of human absorption than the cell-based assays. This method, although time consuming, could be used as a secondary test for studying the mechanisms governing the absorption of new compounds, and for predicting more accurately the fraction absorbed in man.

<div class="section abstract"><div class="htmlview paragraph">Over the last decades, a new class of reusable temporary fasteners having expanding mandrels have come to market. Their large-scale implementation has resulted in these fasteners being utilized in high shear stress environments resulting in the identification of several limitations. Parts shifting as a result of shear forces in the airframe assembly during temporary fastener installation or removal can cause current mandrel-based fasteners to become damaged and difficult to remove from the hole. Additionally, enhanced fastener shear resistance is desirable in very high shear forces environments.</div><div class="htmlview paragraph">This paper examines current mandrel based temporary fasteners while also examining two new concepts in reusable temporary fasteners that are specifically designed to offer mitigations to the aforementioned limitations.</div></div>

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