Intestinal Permeability and Drug Absorption: Predictive Experimental, Computational and In Vivo Approaches

Dahlgren, David; Lennernäs, Hans

doi:10.3390/pharmaceutics11080411

Cited by 148 publications

(113 citation statements)

References 105 publications

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“…When anatoxin-a producing cyanobacterial biofilm are accidently ingested by dogs, the animals present first appearance of neurotoxic symptoms within less than 5 minutes (Wood et al, 2007), testifying for a very rapid assimilation of a toxinogenous dose of anatoxin-a released from the cyanobacterial biomass within the stomach. To date, the genuine mechanism of the anatoxin-a transfer through the intestinal epithelia remains undetermined but the promptitude of the effects suggests that this small molecule (MW = 165 da) may remain uncharged in order to be able to sharply cross the intestinal barrier, potentially through passive paracellular diffusion (Dahlgren and Lennernäs 2019).…”

Section: Discussionmentioning

confidence: 99%

Toxicity, transfer and depuration of anatoxin-a (cyanobacterial neurotoxin) in medaka fish exposed by single-dose gavage

Marie

Colas

Duval

2019

Preprint

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9The proliferations of cyanobacteria are increasingly prevalent in warm and nutrient-enriched 10 waters and occur in many rivers and water bodies due especially to eutrophication. The aim of 11 this work is to study in female medaka fish the toxicity, the transfer and the depuration of the 12 anatoxin-a, a neurotoxin produced by benthic cyanobacterial biofilms. This work will provide 13 answers regarding acute toxicity induced by single gavage by anatoxin-a and to the risks of 14 exposure by ingestion of contaminated fish flesh, considering that data on these aspects remain 15 particularly limited. 16 17The oral LD 50 of a single dose of (±)-anatoxin-a was determined at 11.50 µg.g -1 . First of all, 18lethal dose (100% from 20 µg.g -1 ) provokes rapid respiratory paralysis (in 1-2 min) of the fish 19 inducing the death by asphyxia. Noticeably, no death nor apparent neurotoxicologic effect 20 occurred during the experimentation period for the 45 fish exposed to a single sub-acute dose 21 of (±)-anatoxin-a corresponding to the no observable adverse effect level (NOAEL = 6.67 µg.g -22 1 ). Subsequently, the toxico-kinetics of the (±)-anatoxin-a was observed in the guts, the livers 23 and the muscles of female medaka fish for 10 days. 24In parallel, a protocol for extraction of anatoxin-a has been optimized beforehand by testing 25 3 different solvents on several matrices, the extraction with 75% methanol + 0.1% formic acid 26 appearing to be the most efficient. Anatoxin-a was quantified by high-resolution qTOF mass 27 spectrometry coupled upstream to a UHPLC chromatographic chain. The toxin could not be 28 detected in the liver after 12 h, and in the gut and muscle after 3 days. The mean clearance rates 29 of (±)-anatoxin-a calculated after 12 h are above 58%, 100% and 90% for the guts, the livers 30 and the muscles, respectively. Non-targeted metabolomics investigations performed on the fish 31 liver indicates that the single sub-acute exposure by gavage induces noticeable metabolome 32 dysregulations, including important phospholipid decreases, with an organism recovery period 33 of above 12-24h. Overall, the medaka fish do not appear to accumulate (±)-anatoxin-a and to 34 largely recover after 24h following a single sub-acute oral liquid exposure at the NOAEL. 35 36

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Section: Discussionmentioning

confidence: 99%

Toxicity, transfer and depuration of anatoxin-a (cyanobacterial neurotoxin) in medaka fish exposed by single-dose gavage

Marie

Colas

Duval

2019

Preprint

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“…These conflicting results indicate that parameters other than molecular charge dominate. For instance, passive membrane transport is also affected by paracellular pore selectivity, molecular elongation, and intramolecular hydrogen bonding, which might be better understood using complex molecular dynamic simulations [36]. Consequently, any pH-dependent permeability values determined in the rat SPIP model should be interpreted with care, and a linear pH-permeability relationship should not be used to predict intestinal drug transport and absorption.…”

Section: Blood-to-lumen CL Cr-edta Ratiomentioning

confidence: 99%

Regional Intestinal Drug Permeability and Effects of Permeation Enhancers in Rat

et al. 2020

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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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“…Organic cation transporter 3 (Oct3) duodenum < jejunum < ileum [133] Organic anion transporting polypeptide 3 (Oatp3) highest in jejunum [133] Oligopeptide transporter 1 (PepT1) duodenum > jejunum > ileum [133] Multidrug resistance-associated protein 2 (Mrp2) duodenum > jejunum > ileum [133] Multidrug resistance-associated protein 3 (Mrp 3) duodenum < jejunum < ileum [133] Multidrug resistance-associated protein 4 (Mrp 4) duodenum > ileum > jejunum [88] P-glycoprotein (P-gp) duodenum < jejunum < ileum [26] Organic solute transporter α-β (Ostα,β) duodenum > jejunum > ileum [21] Cytochrome P450 3A (Cyp3a) duodenum~jejunum > ileum [134,135] Estrone sulfatase duodenum > jejunum > ileum [136] Glutathione S-Transferase (Gst) duodenum~jejunum > ileum [137] UDP-Glucuronosyltransferase (Ugt) duodenum~jejunum > ileum [138] Humans ASBT duodenum < ileum [139] OATP2B1 duodenum < ileum [140] PEPT1 slightly increasing jejunum > ileum > duodenum duodenum~ileum [19,139] MCT1 slightly decreasing duodenum > ileum [19] CNT11 CNT2 even duo > ileum [138] OCT1 even [19] OCTN1 duodenum < ileum [138] OCTN2 even [19,139] MRP3 even [19] P-gp ileum > jejunum > proximal [19,25,28,140] BCRP even jejunum > ileum > duodenum [19,55,141] MRP2 mRNA MRP1 protein MRP2 protein slightly decreasing proximal > distal even [19,142] MRP1 to 5 MRP2 to MRP6 MRP4 duodenum < jejunum and ileum [141,143,…”

Section: Transporter/enzyme Segmental Distribution Referencesmentioning

confidence: 99%

The Segregated Intestinal Flow Model (SFM) for Drug Absorption and Drug Metabolism: Implications on Intestinal and Liver Metabolism and Drug–Drug Interactions

2020

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The properties of the segregated flow model (SFM), which considers split intestinal flow patterns perfusing an active enterocyte region that houses enzymes and transporters (<20% of the total intestinal blood flow) and an inactive serosal region (>80%), were compared to those of the traditional model (TM), wherein 100% of the flow perfuses the non-segregated intestine tissue. The appropriateness of the SFM model is important in terms of drug absorption and intestinal and liver drug metabolism. Model behaviors were examined with respect to intestinally (M1) versus hepatically (M2) formed metabolites and the availabilities in the intestine (FI) and liver (FH) and the route of drug administration. The %contribution of the intestine to total first-pass metabolism bears a reciprocal relation to that for the liver, since the intestine, a gateway tissue, regulates the flow of substrate to the liver. The SFM predicts the highest and lowest M1 formed with oral (po) and intravenous (iv) dosing, respectively, whereas the extent of M1 formation is similar for the drug administered po or iv according to the TM, and these values sit intermediate those of the SFM. The SFM is significant, as this drug metabolism model explains route-dependent intestinal metabolism, describing a higher extent of intestinal metabolism with po versus the much reduced or absence of intestinal metabolism with iv dosing. A similar pattern exists for drug–drug interactions (DDIs). The inhibitor or inducer exerts its greatest effect on victim drugs when both inhibitor/inducer and drug are given po. With po dosing, more drug or inhibitor/inducer is brought into the intestine for DDIs. The bypass of flow and drug to the enterocyte region of the intestine after intravenous administration adds complications to in vitro–in vivo extrapolations (IVIVE).

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Intestinal Permeability and Drug Absorption: Predictive Experimental, Computational and In Vivo Approaches

Cited by 148 publications

References 105 publications

Toxicity, transfer and depuration of anatoxin-a (cyanobacterial neurotoxin) in medaka fish exposed by single-dose gavage

Toxicity, transfer and depuration of anatoxin-a (cyanobacterial neurotoxin) in medaka fish exposed by single-dose gavage

Regional Intestinal Drug Permeability and Effects of Permeation Enhancers in Rat

The Segregated Intestinal Flow Model (SFM) for Drug Absorption and Drug Metabolism: Implications on Intestinal and Liver Metabolism and Drug–Drug Interactions

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