scholarly journals Regional Intestinal Drug Permeability and Effects of Permeation Enhancers in Rat

Pharmaceutics ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 242 ◽  
Author(s):  
David Dahlgren ◽  
Maria-Jose Cano-Cebrián ◽  
Tobias Olander ◽  
Mikael Hedeland ◽  
Markus Sjöblom ◽  
...  
Keyword(s):  
Intestinal Permeability ◽  
Large Intestine ◽  
Ethylenediaminetetraacetic Acid ◽  
Sodium Dodecyl ◽  
Intestinal Perfusion ◽  
Permeation Enhancers ◽  
Drug Permeability ◽  
Colonic Absorption ◽  
Single Pass ◽  
Perfusion Model

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.

Prediction of human absorption of a trioxane antimalarial drug (CDRI 99/411) using an in-house validated in situ single-pass intestinal perfusion model

2011 ◽  
Vol 61 (09) ◽  
pp. 532-537 ◽  
Author(s):  
Sheelendra Singh ◽  
Kushalkumar Patel ◽  
Tejaswini Pradhan ◽  
Hefazat Siddiqui ◽  
Shio Singh ◽  
...  
Keyword(s):  
Antimalarial Drug ◽  
Intestinal Perfusion ◽  
Single Pass ◽  
Perfusion Model

scholarly journals The In Vivo Effect of Transcellular Permeation Enhancers on the Intestinal Permeability of Two Peptide Drugs Enalaprilat and Hexarelin

Pharmaceutics ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 99 ◽  
Author(s):  
David Dahlgren ◽  
Markus Sjöblom ◽  
Mikael Hedeland ◽  
Hans Lennernäs
Keyword(s):  
Intestinal Permeability ◽  
Sodium Dodecyl ◽  
Peptide Drugs ◽  
Permeation Enhancers ◽  
Enhanced Absorption ◽  
Oral Peptide Delivery ◽  
Small Model ◽  
Delivery Strategies

Permeation enhancers like sodium dodecyl sulfate (SDS) and caprate increase the intestinal permeability of small model peptide compounds, such as enalaprilat (349 Da). However, their effects remain to be investigated for larger low-permeability peptide drugs, such as hexarelin (887 Da). The objective of this single-pass perfusion study in rat was to investigate the effect of SDS at 5 mg/mL and of caprate administered at different luminal concentrations (5, 10, and 20 mg/mL) and pH (6.5 and 7.4). The small intestinal permeability of enalaprilat increased by 8- and 9-fold with SDS at 5 mg/mL and with caprate at 10 and 20 mg/mL but only at pH 7.4, where the free dissolved caprate concentration is higher than at pH 6.5 (5 vs. 2 mg/mL). Neither SDS nor caprate at any of the investigated luminal concentrations enhanced absorption of the larger peptide hexarelin. These results show that caprate requires doses above its saturation concentration (a reservoir suspension) to enhance absorption, most likely because dissolved caprate itself is rapidly absorbed. The absent effect on hexarelin may partly explain why the use of permeation enhancers for enabling oral peptide delivery has largely failed to evolve from in vitro evaluations into approved oral products. It is obvious that more innovative and effective drug delivery strategies are needed for this class of drugs.

scholarly journals Preparation of Puerarin Chitosan Oral Nanoparticles by Ionic Gelation Method and Its Related Kinetics

Pharmaceutics ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 216 ◽  
Author(s):  
Jie Yan ◽  
Zhi-Yu Guan ◽  
Wei-Feng Zhu ◽  
Ling-Yun Zhong ◽  
Zhuo-Qi Qiu ◽  
...  
Keyword(s):  
In Vitro Release ◽  
Intestinal Perfusion ◽  
Pharmacokinetic Studies ◽  
Ultrasonic Power ◽  
Ionic Gelation ◽  
Single Pass ◽  
Perfusion Model ◽  
Vitro Release

In this paper, as an active ingredient, puerarin chitosan nanoparticles (Pur-CS/TPP-NPs) are prepared by an ionic gelation method. The chitosan (CS) concentration, pH of the CS solution, sodium tripolyphosphate (TPP) concentration, stirring speed, stirring time, ultrasonic power, and dosage are used as single factors for investigation, and the encapsulation efficiency, drug loading capacity, particle size, and polydispersity index (PDI) are used as indicators for investigation. The optimal prescription is determined using the Box–Behnken effect surface design method. The characterization of the best formulation, which is determined via an in vitro release assay and liquid chromatography/tandem mass spectrometry (LC-MS/MS) analysis methods, is used here for pharmacokinetic studies. An in situ single-pass intestinal perfusion model is used to investigate drug absorption in the intestine. After characterization, the morphologies of the nanoparticles are intact. It can be seen from the in vitro release experiments that the equation fitted by the nanoparticles is the Higuchi model, the nanoparticle release process is very stable and without sudden release, indicating that the nanoparticles are well-released in vitro. The pharmacokinetic results and the in situ single-pass intestinal perfusion model study show that the bioavailability and absorption of Pur-CS/TPP-NPs were significantly higher than Pur. Thus, all the results show that the prepared nanoparticles can significantly improve the bioavailability of Pur, and we hope to lay the foundation for the development of new products of Pur.

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