Single-pass intestinal perfusion to establish the intestinal permeability of model drugs in mouse

Escribano, Elvira; Sala, Xavier García; Salamanca, Jorge; Navarro, Claudia Roig; Regué, Josep Queralt

doi:10.1016/j.ijpharm.2012.07.010

Cited by 35 publications

(25 citation statements)

References 20 publications

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“…More recently, Escribano et al have assessed the intestinal perfusion technique in mouse using five model drugs proposed by FDA for establishing the suitability of a permeability method. 39 The investigators showed a high correlation between P eff values of the model drugs in mouse and human. They also found that drug permeabilities in mouse were more similar to the values in human than those obtained in rat, suggesting the use of the mouse perfusion model to classify drugs into their appropriate BCS permeability class.…”

Section: Discussionmentioning

confidence: 98%

Comparison of the Permeability of Metoprolol and Labetalol in Rat, Mouse, and Caco-2 Cells: Use as a Reference Standard for BCS Classification

2013

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The purpose of this study was to investigate labetalol as a potential high permeability reference standard for the application of Biopharmaceutics Classification Systems (BCS). Permeabilities of labetalol and metoprolol were investigated in animal intestinal perfusion models and Caco-2 cell monolayers. After isolating specific intestinal segments, in situ single-pass intestinal perfusions (SPIP) were performed in rats and mice. The effective permeabilities (Peff) of labetalol and metoprolol, an FDA standard for the low/high Peff class boundary, were investigated in two different segments of rat intestine (proximal jejunum and distal ileum), and in the proximal jejunum of mouse. No significant difference was found between Peff of metoprolol and labetalol in the jejunum and ileum of rat (0.33±0.11 ×10−4 vs. 0.38±0.06 ×10−4 and 0.57±0.17 ×10−4 vs. 0.64±0.30 ×10−4 cm/s, respectively) and in the jejunum of mouse (0.55±0.05 ×10−4 vs. 0.59±0.13 ×10−4 cm/s). However, Peff of metoprolol and labetalol were 1.7 and 1.6 times higher in the jejunum of mouse, compared to the jejunum of rat, respectively. Metoprolol and labetalol showed segmental dependent permeability through the rat intestine, with increased Peff in the distal ileum in comparison to the proximal jejunum. Most significantly, Peff of labetalol was found to be concentration dependent. Decreasing concentrations of labetalol in the perfusate resulted in decreased Peff compared to Peff of metoprolol. The intestinal epithelial permeability of labetalol was lower than that of metoprolol in Caco-2 cells at both apical pH 6.5 and 7.5 (5.96±1.96 ×10−6 vs. 9.44±3.44 ×10−6 and 15.9±2.2 ×10−6 vs. 23.2±7.1 ×10−6 cm/s, respectively). Labetalol exhibited higher permeability in basolateral to apical (BL-AP) compared to AP-BL direction in Caco-2 cells at 0.1 times the highest dose strength (HDS) (46.7±6.5 ×10−6 vs. 14.2±1.5 ×10−6 cm/s). The P-gp inhibitor, verapamil significantly increased AP-BL and decreased BL-AP direction transport of labetalol. Overall, labetalol showed high Peff in rat and mouse intestinal perfusion models similar to metoprolol at a concentration based on HDS. However, the concentration dependent permeability of labetalol in mice due to P-gp and the inhibition study with verapamil in Caco-2 cells indicated that labetalol is not an ideal reference standard for BCS classification.

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Section: Discussionmentioning

confidence: 98%

Comparison of the Permeability of Metoprolol and Labetalol in Rat, Mouse, and Caco-2 Cells: Use as a Reference Standard for BCS Classification

2013

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“…The experimental effective intestinal permeability data for various drugs (Table ) were taken from studies performed using SPIP techniques (Table , Table ). The permeability of the drugs tested was determined by measuring either the concentration of drug in the outlet perfusate solution (disappearance of drug, P eff ) or the appearance of the drug in mesenteric blood ( P app ) . Adachi et al measured the permeability surface area (PS) product (μl/min/cm) of numerous drugs in the mouse intestine, and hence this was converted to P eff,mouse (cm/s) as described in Supplement 1.…”

Section: Methodsmentioning

confidence: 99%

“…The mouse effective intestinal permeability ( P eff,mouse ) values were taken from references . The strains of mice used in the studies were mainly FVB (Friend Virus B susceptibility) mice (16 drugs), CD‐1 (Cluster of differentiation 1) mice (5 drugs), NMRI (Naval Medical Research Institute) mice (2 drugs) and an unspecified strain (1 drug).…”

Section: Methodsmentioning

confidence: 99%

Application of the MechPeff model to predict passive effective intestinal permeability in the different regions of the rodent small intestine and colon

Pade

Jamei

Rostami‐Hodjegan

et al. 2017

Biopharm & Drug Disp

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A major component of physiologically based pharmacokinetic (PBPK) models is the prediction of the rate and extent of absorption of orally dosed drugs for which knowledge of effective passive intestinal permeability (P ) is essential. Single-pass intestinal perfusion (SPIP) studies are used to establish effective permeability in vivo but are difficult to perform in rodents, while mechanistic models to predict drug P in rat and mouse have not been published. This work evaluates the predictive performance of the 'MechPeff' model to predict P in the rodent intestine based upon knowledge of regional gut physiology and drug-specific physicochemical parameters. The 'MechPeff' model, built-in to the Simcyp Rat and Mouse Simulators, predicts transcellular, paracellular and mucus layer permeabilities and combines these to give the overall P . The jejunal and/or ileal P was predicted for 12 (4) acidic, 13 (12) basic, 10 (8) neutral and 2 (0) ampholytic drugs in the rat (mouse), spanning a wide range of MW and logP , and compared with experimental P obtained using SPIP. A key input is the intrinsic transcellular permeability (P ) which can be derived from modelling of appropriate in vitro permeability experiments or predicted from physicochemical properties. The P predictions were reasonably good when experimentally derived P was used; from 42 P values, 24 (57%) were within 3-fold, and of 19 P values, 12 (63%) were within 3-fold, of observed P . Considering the lack of alternative models to predict P in preclinical species, and the minimal drug-specific inputs required, this model provides a valuable tool within drug discovery and development programmes. Copyright © 2017 John Wiley & Sons, Ltd.

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“…The absorption mechanism of these two compounds was passive diffusion [16,26,27], suggesting that the drug concentration had no effects on its absorption. Thus, 40 μg/mL of theophylline, ranitidine and NCE perfusion solution were prepared for the SPIP study.…”

Section: Resultsmentioning

confidence: 99%

Study on Biopharmaceutics Classification and Oral Bioavailability of a Novel Multikinase Inhibitor NCE for Cancer Therapy

Yang

Fan

et al. 2014

IJMS

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Specific biopharmaceutics classification investigation and study on phamacokinetic profile of a novel drug candidate (2-methylcarbamoyl-4-{4-[3- (trifluoromethyl) benzamido] phenoxy} pyridinium 4-methylbenzenesulfonate monohydrate, NCE) were carried out. Equilibrium solubility and intrinsic dissolution rate (IDR) of NCE were estimated in different phosphate buffers. Effective intestinal permeability (Peff) of NCE was determined using single-pass intestinal perfusion technique in rat duodenum, jejunum and ileum at three concentrations. Theophylline (high permeability) and ranitidine (low permeability) were also applied to access the permeability of NCE as reference compounds. The bioavailability after intragastrical and intravenous administration was measured in beagle dogs. The solubility of NCE in tested phosphate buffers was quite low with the maximum solubility of 81.73 μg/mL at pH 1.0. The intrinsic dissolution ratio of NCE was 1 × 10−4 mg·min−1·cm−2. The Peff value of NCE in all intestinal segments was more proximate to the high-permeability reference theophylline. Therefore, NCE was classified as class II drug according to Biopharmaceutics Classification System due to its low solubility and high intestinal permeability. In addition, concentration-dependent permeability was not observed in all the segments, indicating that there might be passive transportation for NCE. The absolute oral bioavailability of NCE in beagle dogs was 26.75%. Therefore, dissolution promotion will be crucial for oral formulation development and intravenous administration route will also be suggested for further NCE formulation development. All the data would provide a reference for biopharmaceutics classification research of other novel drug candidates.

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Single-pass intestinal perfusion to establish the intestinal permeability of model drugs in mouse

Cited by 35 publications

References 20 publications

Comparison of the Permeability of Metoprolol and Labetalol in Rat, Mouse, and Caco-2 Cells: Use as a Reference Standard for BCS Classification

Comparison of the Permeability of Metoprolol and Labetalol in Rat, Mouse, and Caco-2 Cells: Use as a Reference Standard for BCS Classification

Application of the MechPeff model to predict passive effective intestinal permeability in the different regions of the rodent small intestine and colon

Study on Biopharmaceutics Classification and Oral Bioavailability of a Novel Multikinase Inhibitor NCE for Cancer Therapy

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