Transport of levovirin prodrugs in the human intestinal Caco-2 cell line

Li, Fujun; Lü, Hong; Mau, Cheng-I; Chan, Rebecca Wing-Yan; Hendricks, Than; Dvorak, Charles A.; Yee, Calvin; Harris, Jason; Alfredson, Tom

doi:10.1002/jps.20434

Cited by 40 publications

(27 citation statements)

References 23 publications

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“…The high, mean end flux of enalapril may be explained by the combination of passive and active mucosal transport processes. Caco-2 cells are the most advanced and frequently used cell model to predict small-intestine drug permeability and absorption (31)(32)(33). Compared to Caco-2 cells, the present in vitro assay do not have drawbacks such as long cell growth cycles, possibility of microbial contamination, high costs, and relatively wide inter-experiment and inter-laboratory variations, which limit Caco-2 cells as high-throughput screening systems.…”

Section: Discussionmentioning

confidence: 99%

Permeation of Four Oral Drugs Through Human Intestinal Mucosa

Pretorius

Bouic

2009

AAPS PharmSciTech

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Abstract. The pharmaceutical industry is in need of rapid and accurate methods to screen new drug leads for intestinal permeability potential in the early stages of drug discovery. Excised human jejunal mucosa was used to investigate the permeability of the small intestine to four oral drugs, using a flow-through diffusion system. The four drugs were selected as representative model compounds of drug classes 1 and 3 according to the biopharmaceutics classification system (BCS). The drugs selected were zidovudine, propranolol HCl, didanosine, and enalapril maleate. Permeability values from our in vitro diffusion model were compared with the BCS permeability classification and in vivo and in vitro gastrointestinal drug permeability. The flux rates of the four drugs were influenced by the length of the experiment. Both class 1 drugs showed a significantly higher mean flux rate between 2 and 6 h across the jejunal mucosa compared to the class 3 drugs. The results are therefore in line with the drugs' BCS classification. The results of this study show that the permeability values of jejunal mucosa obtained with the flow-through diffusion system are good predictors of the selected BCS class 1 and 3 drugs' permeation, and it concurred with other in vitro and in vivo studies.

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Section: Discussionmentioning

confidence: 99%

Permeation of Four Oral Drugs Through Human Intestinal Mucosa

Pretorius

Bouic

2009

AAPS PharmSciTech

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“…preparing and utilizing a prodrug) or modulating the membrane properties (e.g. using a permeability enhancer) have been used (Li et al 2006). Due to the complexity of cell membranes, it might be difficult to fully elucidate the exact mechanism of action by which different excipients affect membrane permeability.…”

Section: Excipients For Improving the Permeability Of Bcs Class Iii/imentioning

confidence: 99%

Selection of Excipients Based on the Biopharmaceutics Classification System of Drugs

Baki

Chaudhari²,

Gaudana

et al. 2015

Excipient Applications in Formulation Design and Drug Delivery

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Active agents have been considered the main ingredients of any therapeutic product since the early ages of formulation technology. However, the importance of the inactive ingredients has been realized during the last three decades. With the development and manufacturing of more intelligent and multifunction excipients, new ways became available for formulation technologists to increase the beneficial effects of drugs on human body. Many modern active agents have internal characteristics that significantly decrease their potential and theoretical bioavailability; however, today we have the widest variety of inactive ingredients that we can utilize in order to change these properties. The careful and educated selection of excipients might significantly influence the effect of the drugs, including hastening or delaying their onset of action, increasing their bioavailability by changing their physicochemical characteristics, and increasing their stability. In this chapter, we focus primarily on the factors determining and influencing bioavailability as well as the selection of excipients for formulating new dosage forms with enhanced therapeutic efficacy, based on the physicochemical properties of drugs. We will provide some examples from the scientific literature to demonstrate the achievements in this multidisciplinary area.

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“…The human cell line Caco-2, in particular, has shown to be a suitable and reliable model for this kind of studies 14 , as it is derived from human colon adenocarcinoma cells and exhibits several classes of different markers typically found in adult's intestinal differentiated cells (e.g., alkaline phosphatase and microvilli in the brush border) [15][16][17][18][19] . In fact, the use of Caco-2 cells in cytotoxicity evaluation experiments presents several advantages: (i) there are no significant differences in either the morphological or physiological characteristics of intestinal cancer cells compared to normal cells 15,20 ; (ii) it allows to gather information on the potential drug's toxicity toward the mucosa [21][22][23] ; (iii) it provides information, at the cellular level, on drug's absorption, metabolism, and transport through the intestinal wall [24][25][26][27][28][29] .…”

Section: Research Articlementioning

confidence: 99%

New sustained release of Zidovudine Matrix tablets − cytotoxicity toward Caco-2 cells

Santos¹,

Pina²,

Marques³

et al. 2012

Drug Development and Industrial Pharmacy

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Objective: The aim of this study was to adjust the zidovudine (AZT) release from solid tablets to an ideal profile, by developing matrices comprising swellable polymers with nonswellable ones.Methods: Directly compressed matrices comprised different ratios of hydroxypropylmethylcellulose K15M and K100M, ethylcellulose, and methacrylic acid (Eudragit® RS PO and Eudragit® RL PO) were prepared. Technological characterization and evaluation of the in vitro release behavior were carried out. Cell density and viability following drug exposure were evaluated by the SRB method, for the Caco-2 line, while cell morphology was assessed upon Trypan blue staining.Results: A specific formulation containing 5% of each excipient − HPMC K15M, HPMC K100M, Eudragit® RS PO, and Eudragit® RL PO − was found to yield the best release profile. Application of the Korsmeyer-Peppas model to the dissolution profile evidenced that a non-Fickian (anomalous) transport is involved in the drug release. Regarding the influence of the tablets' composition on the drug's cytotoxic effect toward the Caco-2 cell line, a reduction of cell biomass (0-15%) was verified for the distinct AZT formulations tested, F19 having displayed the highest cytotoxicity, after 24 and 48 h of incubation. Additionally, a high reversibility of the AZT effect was observed. Conclusions:The results showed that the simultaneous application of both hydrophilic and hydrophobic polymers can modulate the drug release process, leading to an improved efficacy and patient compliance. All AZT formulations studied were found to be cytotoxic against Caco-2 cells, F19 being the most effective one.

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Transport of levovirin prodrugs in the human intestinal Caco-2 cell line

Cited by 40 publications

References 23 publications

Permeation of Four Oral Drugs Through Human Intestinal Mucosa

Permeation of Four Oral Drugs Through Human Intestinal Mucosa

Selection of Excipients Based on the Biopharmaceutics Classification System of Drugs

New sustained release of Zidovudine Matrix tablets − cytotoxicity toward Caco-2 cells

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