Regional Intestinal Drug Permeability and Effects of Permeation Enhancers in Rat

Abstract

Sufficient colonic absorption is necessary for all systemically acting drugs in dosage forms that release the drug in the large intestine. Preclinically, colonic absorption is often investigated using the rat single-pass intestinal perfusion model. This model can determine intestinal permeability based on luminal drug disappearance, as well as the effect of permeation enhancers on drug permeability. However, it is uncertain how accurate the rat single-pass intestinal perfusion model predicts regional intestinal permeability and absorption in human. There is also a shortage of systematic in vivo investigations of the direct effect of permeation enhancers in the small and large intestine. In this rat single-pass intestinal perfusion study, the jejunal and colonic permeability of two low permeability drugs (atenolol and enalaprilat) and two high-permeability ones (ketoprofen and metoprolol) was determined based on plasma appearance. These values were compared to already available corresponding human data from a study conducted in our lab. The colonic effect of four permeation enhancers-sodium dodecyl sulfate, chitosan, ethylenediaminetetraacetic acid (EDTA), and caprate-on drug permeability and transport of chromium EDTA (an established clinical marker for intestinal barrier integrity) was determined. There was no difference in jejunal and colonic permeability determined from plasma appearance data of any of the four model drugs. This questions the validity of the rat single-pass intestinal perfusion model for predicting human regional intestinal permeability. It was also shown that the effect of permeation enhancers on drug permeability in the colon was similar to previously reported data from the rat jejunum, whereas the transport of chromium EDTA was significantly higher (p < 0.05) in the colon than in jejunum. Therefore, the use of permeation enhancers for increasing colonic drug permeability has greater risks than potential medical rewards, as indicated by the higher permeation of chromium EDTA compared to the drugs.Pharmaceutics 2020, 12, 242 2 of 14 frequently used in pharmaceutical development to evaluate the potential success of a drug, for instance with oral modified-release (MR) dosage forms. In MR dosage forms, the drug is released throughout the gastrointestinal (GI) tract prior to absorption so the regional intestinal permeability needs to be sufficiently high in both the small and large intestine. The rat and human small intestine have similar drug intestinal absorption profiles and transporter expression patterns, but differ in their enzymatic metabolism [2]. Differences in absorption from the rat and human colon have not been extensively compared, but a recent meta-analysis of rat SPIP data reports regional differences in drug permeability for 42 drugs in this species [3].How relevant for humans are the regional intestinal drug permeability values determined in the rat SPIP model? It is difficult to answer this because of the limited amount of human reference permeability data from the lower GI trac...

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