Comparative Studies of the Enhancing Effects of Cyclodextrins on the Solubility and Oral Bioavailability of Tacrolimus in Rats

Arima, Hisatomi; Yunomae, Kiyokazu; Miyake, Kouzou; Irie, Tetsumi; Hirayama, Fumitoshi; Uekama, Kaneto

doi:10.1002/jps.1025

Cited by 128 publications

(80 citation statements)

References 31 publications

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“…Caco-2 cells (passages 40 and 60) were obtained from the American Type Culture Collection and cultivated as reported previously [13]. Abbreviations: AP-to-BL, apical to basolateral; BCECF, 2P,7P-bis(2-carboxyethyl)-5(6)-carboxy£uorescein; BCECF-AM, 2P,7P-bis(2-carboxyethyl)-5(6)-carboxy£uorescein acetoxymethylester; BL-to-AP, basolateral to apical; CyDs, cyclodextrins; DS, degree of substitution; DM-L-CyD, 2,6-di-O-methyl-L-cyclodextrin; HP-K-CyD, 2-hydroxypropyl-K-cyclodextrin; HP-L-CyD, 2-hydroxypropyl-L-cyclodextrin; HP-Q-CyD, 2-hydroxypropyl-Q-cyclodextrin; HPLC, high performance liquid chromatography; MRP2, multidrug resistance-associated protein 2; M-L-CyD, methyl-L-cyclodextrin; MBS, MES-bu¡ered saline; MDR, multidrug-resistant; P app , apparent permeability coe⁄cient; P-gp, P-glycoprotein; RT-PCR, reverse transcription polymerase reaction; SDS, sodium dodecyl sulfate; TEER, transepithelial electric resistance The e¡ects of CyDs on viability and integrity of Caco-2 cell monolayers were measured as reported previously [17].…”

Section: Cytotoxicity and Transepithelial Electrical Resistance (Teer)mentioning

confidence: 99%

“…The e¡ects of treating with CyDs on the transport of [ 3 H]mannitol (speci¢c activity, 19.7 Ci/Wmol, New England Nuclear) and the e¡ects of pretreatment with CyDs on the rhodamine 123 (Molecular Probes) and BCECF (2P,7P-bis(2-carboxyethyl)-5(6)-carboxy£uorescein; Molecular Probes) across Caco-2 cell monolayers were studied as described previously [13]. Brie£y, [ 3 H]mannitol was added to the apical side's transport bu¡er in the absence and presence of CyDs and incubated for 60 min.…”

Section: Transport Studiesmentioning

confidence: 99%

“…The concentrations of rhodamine 123 and BCECF in the transport bu¡er were determined by a high performance liquid chromatography (HPLC) and a Hitachi F-4500 £uo-rophotometer (excitation and £uorescence wavelengths were 439 nm and 525 nm, respectively), respectively. The HPLC conditions were the same as that reported previously [13]. The apparent permeability coe⁄cient (P app ) was calculated using the following equation:…”

Section: Transport Studiesmentioning

confidence: 99%

“…We recently demonstrated that 2,6-di-O-methyl-L-cyclodextrin (DM-L-CyD) signi¢cantly increased the low aqueous solubility and oral bioavailability of tacrolimus, an immunosuppressive agent, in rats and the improvement in oral bioavailability was due not only to its solubilizing e¡ect but also, at least in part, to its inhibitory e¡ect on the P-gp-mediated e¥ux of tacrolimus from intestinal epithelial cells [13]. P-gp is reported to be localized in caveolae, £ask-shaped invaginations, in which cholesterol and glycosphingolipids are abundant in multidrug-resistant (MDR) cells and in brain capillaries [14,15].…”

Section: Introductionmentioning

confidence: 99%

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Involvement of cholesterol in the inhibitory effect of dimethyl‐β‐cyclodextrin on P‐glycoprotein and MRP2 function in Caco‐2 cells

et al. 2003

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We compared the inhibitory e¡ect of various cyclodextrins (CyDs) on P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2) function and examined the contribution of cholesterol to the inhibitory e¡ect of 2,on the e¥ux activity of the function in Caco-2 cell monolayers. Of various CyDs, DM-L LCyD signi¢cantly impaired the e¥ux activity of P-gp and MRP2. DM-L L-CyD released P-gp and MRP2 from the monolayers in the apical side's transport bu¡er and decreased the extent of cholesterol as well as P-gp and MRP2 in caveolae of Caco-2 cell monolayers, but not caveolin and £otillin-1. On the other hand, DM-L L-CyD did not change MDR1 and MRP2 mRNA levels. Therefore, these results suggest that the inhibitory e¡ect of DM-L L-CyD on P-gp and MRP2 function, at least in part, could be attributed to the release of these transporters from the apical membranes into the medium as secondary e¡ects through cholesterol-depletion in caveolae after treatment of Caco-2 cell monolayers with DM-L L-CyD. ß

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Section: Cytotoxicity and Transepithelial Electrical Resistance (Teer)mentioning

confidence: 99%

Section: Transport Studiesmentioning

confidence: 99%

Section: Transport Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Involvement of cholesterol in the inhibitory effect of dimethyl‐β‐cyclodextrin on P‐glycoprotein and MRP2 function in Caco‐2 cells

et al. 2003

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“…Solubilisation of amphotericin B using polymeric micelles, has resulted in a reduced haemolytic activity of the drug (Yu et al 1998). Similarly the use of cyclodextrins to enhance the gastrointestinal absorption of tacrolimus was shown to reduce renal and neural toxicity in rats (Arima et al 2001).…”

Section: Introductionmentioning

confidence: 99%

Using random forest and decision tree models for a new vehicle prediction approach in computational toxicology

et al. 2015

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Drug vehicles are chemical carriers that provide beneficial aid to the drugs they bear. Taking advantage of their favourable properties can potentially allow the safer use of drugs that are considered highly toxic. A means for vehicle selection without experimental trial would therefore be of benefit in saving time and money for the industry. Although machine learning is increasingly used in predictive toxicology, to our knowledge there is no reported work in using machine learning techniques to model drug-vehicle relationships for vehicle selection to minimise toxicity. In this paper we demonstrate the use of data mining and machine learning techniques to process, extract and build models based on classifiers (decision trees and random forests) that allow us to predict which vehicle would be most suited to reduce a drug's toxicity. Using data acquired from the National Institute of Health's (NIH) Developmental Therapeutics Program (DTP) we propose a methodology using an area under a curve (AUC) approach that allows us to distinguish which vehicle provides the best toxicity profile for a drug and build classification models based on this knowledge. Our results show that we can achieve prediction accuracies of 80 % using random forest models whilst the decision tree models produce Communicated by D. Neagu. Electronic supplementary materialThe online version of this article (doi:10.1007/s00500-015-1925-9) contains supplementary material, which is available to authorized users.

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Electronic Circular Dichroism Spectroscopy

Zsila¹

2010

Pharmaceutical Sciences Encyclopedia

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Electronic circular dichroism (ECD or CD) is the manifestation of the important property of chiral compounds to absorb left and right circularly polarized light to different extents. Electronic circular dichroism (CD) spectroscopy technique has been used for investigation of chiral drugs and other pharmaceutical preparations. This article focuses on basic features, instrumentation, advantages, limitations, and practical applications of electronic circular dichroism (CD) spectroscopy in pharmaceutical sciences.

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Comparative Studies of the Enhancing Effects of Cyclodextrins on the Solubility and Oral Bioavailability of Tacrolimus in Rats

Cited by 128 publications

References 31 publications

Involvement of cholesterol in the inhibitory effect of dimethyl‐β‐cyclodextrin on P‐glycoprotein and MRP2 function in Caco‐2 cells

Involvement of cholesterol in the inhibitory effect of dimethyl‐β‐cyclodextrin on P‐glycoprotein and MRP2 function in Caco‐2 cells

Using random forest and decision tree models for a new vehicle prediction approach in computational toxicology

Electronic Circular Dichroism Spectroscopy

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