Validation of a differential <i>in situ</i> perfusion method with mesenteric blood sampling in rats for intestinal drug interaction profiling

Brouwers, Joachim; Mols, Rafaël; Annaert, Pieter; Augustijns, Patrick

doi:10.1002/bdd.710

Cited by 17 publications

(12 citation statements)

References 28 publications

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“…Single-pass intestinal perfusion was performed in anesthetized rats according to the method described by Brouwers et al [15], with simultaneous sampling from the luminal perfusate and mesenteric blood.…”

Section: Single-pass Intestinal Perfusion Studiesmentioning

confidence: 99%

“…This experimental model, which includes a mucus layer, blood irrigation and innervation, has been widely used due to its similarity with in vivo conditions [14]. It also allows the study of the role of transporters in absorption through the biorelevant expression of proteins (both transporters and intestinal enzymes) [12,15] and has full metabolic capacity for up to 120 min after intestinal isolation [16].…”

Section: Introductionmentioning

confidence: 99%

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Absorption and Intestinal Metabolic Profile of Oleocanthal in Rats

et al. 2020

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Oleocanthal (OLC), a phenolic compound of extra virgin olive oil (EVOO), has emerged as a potential therapeutic agent against a variety of diseases due to its anti-inflammatory activity. The aim of the present study is to explore its in vivo intestinal absorption and metabolism. An in situ perfusion technique in rats was used, involving simultaneous sampling from the luminal perfusate and mesenteric blood. Samples were analysed by UHPLC–MS–MS for the presence of oleocanthal (OLC) and its metabolites. OLC was mostly metabolized by phase I metabolism, undergoing hydration, hydrogenation and hydroxylation. Phase II reactions (glucuronidation of hydrogenated OLC and hydrated metabolites) were observed in plasma samples. OLC was poorly absorbed in the intestine, as indicated by the low effective permeability coefficient (2.23 ± 3.16 × 10−5 cm/s) and apparent permeability coefficient (4.12 ± 2.33 × 10−6 cm/s) obtained relative to the values of the highly permeable reference compound levofloxacin (LEV). The extent of OLC absorption reflected by the area under the mesenteric blood-time curve normalized by the inlet concentration (AUC) was also lower than that of LEV (0.25 ± 0.04 vs. 0.64 ± 0.03, respectively). These results, together with the observed intestinal metabolism, suggest that OLC has a moderate-to-low oral absorption; but higher levels of OLC are expected to reach human plasma vs. rat plasma.

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Section: Single-pass Intestinal Perfusion Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Absorption and Intestinal Metabolic Profile of Oleocanthal in Rats

et al. 2020

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“…The P eff values of NCE were more proximate to that of theophylline with high permeability, suggesting that NCE has a high permeability. The permeability coefficients of NCE obtained from SPIP study in three intestinal segments at three different concentrations, with the minimum of P eff (0.20 × 10 −4 cm/s) found in jejunum and the maximal P eff (0.56 × 10 −4 cm/s) found in duodenum, were comparable to propranolol ( P eff of propranolol: 0.30–0.75 × 10 −4 cm/s) which was a widely used reference compound for high permeability evaluation [4,28]. Hence, NCE was considered to be well absorbed in the whole intestine and categorized as a high permeability drug.…”

Section: Resultsmentioning

confidence: 99%

“…The essential parameters controlling oral drug absorption are the permeability of the drug through the gastrointestinal (GI) membrane and the drug solubility/dissolution in GI milieu [2,3]. Biopharmaceutics Classification System (BCS) is a modern tool to characterize drug permeability and solubility/dissolution [4,5]. According to BCS, drugs are characterized into four categories: Class I—high permeability, high solubility; Class II—high permeability, low solubility; Class III—low permeability, high solubility; Class IV—low permeability, low solubility.…”

Section: Introductionmentioning

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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“…Talinolol was extracted from the blood samples and quantified by means of high-performance liquid chromatography (HPLC) with fluorescence detection according to earlier described procedures (Brouwers et al, 2010). Darunavir samples were analyzed using an HPLC method with fluorescence detection.…”

Section: Discussionmentioning

confidence: 99%

Hepatobiliary and intestinal elimination of darunavir in an integrated preclinical rat model

Stappaerts¹,

Fattah²,

Annaert³

et al. 2013

Xenobiotica

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1. Although valuable in vitro models exist to study drug elimination from the systemic circulation, more integrated models may improve mechanistic insight in a biorelevant setting. 2. This study aimed to explore (1) intestinal and biliary excretion of the HIV protease inhibitor darunavir and its impact on systemic disposition and (2) to evaluate to what extent findings in an in situ excretion model in rat can be captured by individual in vitro models. 3. Contemporary in vitro models were applied to study intestinal and hepatobiliary disposition of darunavir and data were compared with findings in the in situ excretion model. 4. Both in situ and in vitro experiments demonstrated significant metabolism of darunavir, which could be strongly inhibited by the P450 inhibitor 1-aminobenzotriazole. Using the P-gp inhibitor zosuquidar, P-gp mediated excretion of darunavir from blood towards gastrointestinal lumen was evidenced and this was confirmed by transport studies in Caco-2 cells. Moreover, involvement of P-gp in the biliary excretion of darunavir was also demonstrated in situ. 5. In general, in situ findings corresponded well with in vitro data. The in situ excretion model offers the possibility to gain mechanistic insight in intestinal and hepatobiliary excretion processes and, at the same time, evaluate their impact on the systemic disposition of a compound.

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Validation of a differential in situ perfusion method with mesenteric blood sampling in rats for intestinal drug interaction profiling

Cited by 17 publications

References 28 publications

Absorption and Intestinal Metabolic Profile of Oleocanthal in Rats

Absorption and Intestinal Metabolic Profile of Oleocanthal in Rats

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

Hepatobiliary and intestinal elimination of darunavir in an integrated preclinical rat model

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