Determination of site of absorption of propranolol in rat gut using In situ single-pass intestinal perfusion

Nagare, N; Damre, Anagha; Singh, K. P.; Mallurwar, Sadanand Rangnathrao; Iyer, Seethalakshmi; Naik, Aarti; Chintamaneni, Meena

doi:10.4103/0250-474x.78533

Cited by 24 publications

(9 citation statements)

References 14 publications

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“…Generally, a compound with a P eff value greater than 1.5 × 10 −4 cm/s is considered to be absorbed well, regardless of which transport mechanisms are utilized (Lennernäs, ). Furthermore, the permeability coefficients of GL‐V9 obtained from the in situ single‐pass intestinal perfusion model were comparable to the reported values of propranolol (a reference compound of passive absorption by the transcellular pathway, 0.33−0.72 × 10 −4 cm/s) (Damre et al, ). The P eff of GL‐V9 through the jejunum was 1.34 ± 0.50 × 10 −4 cm/s, indicating that GL‐V9 could be well absorbed in the jejunum at a concentration of 1 μM.…”

Section: Discussionsupporting

confidence: 83%

Mechanistic study of absorption and first‐pass metabolism of GL‐V9, a derivative of wogonin

Xing

Ren

Kong

et al. 2019

Biopharm & Drug Disp

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GL-V9, a derivative of wogonin, has potent anti-cancer activity. The absorption and metabolism of this compound have not been investigated systematically. This study aims to illustrate the pharmacokinetic characters of GL-V9 by exploring its metabolic status under different administration routes. To further clarify the absorption mechanism of GL-V9, an in situ single-pass perfusion model and a Caco-2 cell monolayer model were used. Meanwhile, a microsomal incubation system was used to evaluate the enzyme kinetic parameters. In vivo, the obtained gastrointestinal availability (F a × F g ) was 21.28 ± 5.38%. The unmetabolized fraction in the gut wall (F gut wall ) was 98.59 ± 9.74%, while the hepatic bioavailability (F h ) was 29.11 ± 5.22%. These results indicated that poor absorption and extensive metabolism may contribute greatly to the low bioavailability of GL-V9. The effective permeability (P eff ) in the duodenum and jejunum was 1.34 ± 0.50 × 10 −4 and 0.90 ± 0.27 × 10 −4 cm/s, respectively. The high permeability of GL-V9 indicated that other unknown factors (such as metabolism) may account for its systemic exposure problem. Studies in rat liver microsomal (RLMs) confirmed this hypothesis, and the Cl int, CYP450s and UGT of GL-V9 was 0.20 ml/min/mg protein. In conclusion, these results suggest that GL-V9 possesses higher permeability than wogonin and the metabolism of GL-V9 is related to its disposition in rat intestine and liver.

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Section: Discussionsupporting

confidence: 83%

Mechanistic study of absorption and first‐pass metabolism of GL‐V9, a derivative of wogonin

Xing

Ren

Kong

et al. 2019

Biopharm & Drug Disp

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“…ATL and PPL are beta-blockers used to treat hypertension and are also commonly used as substrates for para- and transcellular transport (ATL-paracellular, PPL-transcellular). 32,33 The high P app of PPL measured for the day-5 monolayers suggested transcellular transport for this drug as highly permeable compounds exhibit P app >2×10 −6 cm s −1 (Figure 4A). 17 The P app of ATL indicated a low permeability similar to that of LY (Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

A Monolayer of Primary Colonic Epithelium Generated on a Scaffold with a Gradient of Stiffness for Drug Transport Studies

Gunasekara

Speer²,

Wang³

et al. 2018

Anal. Chem.

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Animal models are frequently used for in vitro physiologic and drug transport studies of the colon, but there exists significant pressure to improve assay throughput as well as achieve tighter control of experimental variables than can be achieved with animals. Thus development of a primary in vitro colonic epithelium cultured as a high-resistance with transport protein expression and functional behavior similar to that of native colonic would be of enormous value for pharmaceutical research. A collagen scaffold in which the degree of collagen cross-linking was present as a gradient was developed to support the proliferation of primary colonic cells. The gradient of cross-linking created a gradient in stiffness across the scaffold enabling the scaffold to resist deformation by cells. mRNA expression and quantitative proteomic mass spectrometry of cells growing on these surfaces as a monolayer suggested that the transporters present were similar to those in vivo. Confluent monolayers acted as a barrier to small molecules so that drug transport studies were readily performed. Transport function was evaluated using atenolol (a substrate for passive paracellular transport), propranolol (a substrate for passive transcellular transport), rhodamine 123 (Rh123, a substrate for P-glycoprotein) and riboflavin (a substrate for solute carrier transporters). Atenolol was poorly transported with an apparent permeability (Papp) of < 5×10−7 cm s−1 while, propranolol demonstrated a Papp of 9.69×10−6 cm s-1. Rh123 was transported in a luminal direction (Papp, efflux/Papp, influx =7) and was blocked by verapamil, a known inhibitor of P-glycoprotein. Riboflavin was transported in a basal direction and saturation of the transporter was observed at high riboflavin concentrations as occurs in vivo. It is anticipated that this platform of primary colonic epithelium will find utility in drug development and physiological studies since the tissue possesses high integrity and active transporters and metabolism similar to that in vivo.

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“…In the next phase of investigations, transport experiments were carried out for all compounds at a concentration of 30 μg·mL −1 for propranolol as the reference substance [22,23] and 100 and 250 mg·mL −1 for SEV-SBEβCD with transport buffer as the pEND medium or heat-inactivated human serum for an experimental time of 120 min. The amounts of transport substance over time of propranolol and SEV-SBEβCD complex under sink conditions (10% and 5% of human serum were presented on apical and basolateral sides, respectively) are displayed in Figure 6.…”

Section: Resultsmentioning

confidence: 99%

Sevoflurane-Sulfobutylether-β-Cyclodextrin Complex: Preparation, Characterization, Cellular Toxicity, Molecular Modeling and Blood-Brain Barrier Transport Studies

Shityakov

Puskás

Pápai³

et al. 2015

Molecules

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Abstract:The objective of the present investigation was to study the ability of sulfobutylether-β-cyclodextrin (SBEβCD) to form an inclusion complex with sevoflurane (SEV), a volatile anesthetic with poor water solubility. The inclusion complex was prepared, characterized and its cellular toxicity and blood-brain barrier (BBB) permeation potential of the formulated SEV have also been examined for the purpose of controlled drug delivery. The SEV-SBEβCD complex was nontoxic to the primary brain microvascular endothelial (pEND) cells at a clinically relevant concentration of sevoflurane. The inclusion complex exhibited significantly higher BBB permeation profiles as compared with the reference substance (propranolol) concerning calculated apparent permeability values (Papp). In addition, SEV binding affinity to SBEβCD was confirmed by a minimal Gibbs free energy of binding (ΔGbind) value of −1.727 ± 0.042 kcal·mol and an average binding constant (Kb) of 53.66 ± 9.24 mM indicating rapid drug liberation from the cyclodextrin amphiphilic cavity.

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Determination of site of absorption of propranolol in rat gut using In situ single-pass intestinal perfusion

Cited by 24 publications

References 14 publications

Mechanistic study of absorption and first‐pass metabolism of GL‐V9, a derivative of wogonin

Mechanistic study of absorption and first‐pass metabolism of GL‐V9, a derivative of wogonin

A Monolayer of Primary Colonic Epithelium Generated on a Scaffold with a Gradient of Stiffness for Drug Transport Studies

Sevoflurane-Sulfobutylether-β-Cyclodextrin Complex: Preparation, Characterization, Cellular Toxicity, Molecular Modeling and Blood-Brain Barrier Transport Studies

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