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Intestinal membrane transporter-mediated approaches to improve oral drug delivery
PANGENI RUDRA,Kang Soim,JHA SAURAV KUMAR,SUBEDI LAXMAN,박진우 한국약제학회 2021 Journal of Pharmaceutical Investigation Vol.51 No.2
Background Effective oral delivery of drugs remains a major challenge given their possible undesirable physicochemical properties, physicochemical factors, and the physiological conditions of the gastrointestinal (GI) tract. Continuous efforts have been made to overcome these issues by improving the intestinal permeability and oral bioavailability of drugs. Recently, the strategy to improve intestinal permeability has shifted towards targeting drugs to intestinal membrane transporters. Area covered In this review, the usefulness of various solute carrier (SLC) and ATP (adenosine triphosphate)-binding cassette (ABC) transporters that are widely expressed in the intestinal epithelia and their impact on increasing the membrane permeability and oral bioavailability of drugs are discussed. Expert opinion Targeting intestinal membrane transporters has emerged as a promising avenue to increase the oral absorption of drugs. Recently, several approaches that target intestinal membrane transporters have resulted in significant improvements in oral bioavailability, such as the use of absorption enhancers or excipients, modification of a drug’s physicochemical properties, and/or the development of novel drug delivery vehicles that enhance drug influx and inhibit efflux. Additionally, efforts have been made to elucidate the role of dual-transporter targeting in drug delivery. Therefore, implementation of transporter-mediated drug-delivery strategies may be a promising approach to increase oral bioavailability.
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Seho Kweon,Jun‑Hyuck Lee,양성빈,박성진,Laxman Subedi,Jung‑Hyun Shim,Seung‑Sik Cho,Jeong Uk Choi,Youngro Byun,박주호,박진우 한국생체재료학회 2023 생체재료학회지 Vol.27 No.00
Background Despite the effectiveness of glucagon-like peptide-1 agonist (GLP-1A) in the treatment of diabetes, its large molecular weight and high hydrophilicity result in poor cellular permeability, thus limiting its oral bioavailability. To address this, we developed a chimeric GLP-1A that targets transporter-mediated endocytosis to enhance cellular permeability to GLP-1A by utilizing the transporters available in the intestine, particularly the apical sodium-dependent bile acid transporter (ASBT). Methods In silico molecular docking and molecular dynamics simulations were used to investigate the binding interactions of mono-, bis-, and tetra-deoxycholic acid (DOCA) (monoDOCA, bisDOCA, and tetraDOCA) with ASBT. After synthesizing the chimeric GLP-1A-conjugated oligomeric DOCAs (mD-G1A, bD-G1A, and tD-G1A) using a maleimide reaction, in vitro cellular permeability and insulinotropic effects were assessed. Furthermore, in vivo oral absorption in rats and hypoglycemic effect on diabetic db/db mice model were evaluated. Results In silico results showed that tetraDOCA had the lowest interaction energy, indicating high binding affinity to ASBT. Insulinotropic effects of GLP-1A-conjugated oligomeric DOCAs were not different from those of GLP-1A-Cys or exenatide. Moreover, bD-G1A and tD-G1A exhibited improved in vitro Caco-2 cellular permeability and showed higher in vivo bioavailability (7.58% and 8.63%) after oral administration. Regarding hypoglycemic effects on db/db mice, tD-G1A (50 μg/kg) lowered the glucose level more than bD-G1A (50 μg/kg) compared with the control (35.5% vs. 26.4%). Conclusion GLP-1A was conjugated with oligomeric DOCAs, and the resulting chimeric compound showed the potential not only for glucagon-like peptide-1 receptor agonist activity but also for oral delivery. These findings suggest that oligomeric DOCAs can be used as effective carriers for oral delivery of GLP-1A, offering a promising solution for enhancing its oral bioavailability and improving diabetes treatment.
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