Concomitant solubility-permeability increase: Vitamin E TPGS vs. amorphous solid dispersion as oral delivery systems for etoposide

Beig, Avital; Fine-Shamir, Noa; Porat, Daniel; Lindley, David; Miller, Jonathan M.; Dahan, Arik

doi:10.1016/j.ejpb.2017.09.012

Cited by 45 publications

(32 citation statements)

References 48 publications

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“…An interplay between the 2 parameters determines whether the drug moiety will undergo absorption or not. [58][59][60][61][62] Knowing the range of Log p values where the drug is lipophilic enough, but still gets dissolved in the GIT is crucial for absorption. Hence, Log p or some other representation of lipophilicity is included in practically any drug absorption model.…”

Section: In Silico Model Settingsmentioning

confidence: 99%

Segmental-Dependent Intestinal Drug Permeability: Development and Model Validation of In Silico Predictions Guided by In Vivo Permeability Values

Wolk

Marković

Porat

et al. 2019

Journal of Pharmaceutical Sciences

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The goal of this work was to develop an in silico model that allows predicting segmental-dependent permeability throughout the small intestine (SI). In vivo permeability of 11 model drugs in 3 SI segments (jejunum, mid-SI, ileum) was studied in rats, creating a data set that reflects the conditions throughout the SI. Then, a predictive model was developed, combining physicochemical drug properties influencing the underlying mechanism of passive permeability: Log p, polar surface area, M, H-bond count, and Log f, with microenvironmental SI conditions. Excellent correlation was evident between the predicted and experimental data (R = 0.914), with similar predictability in each SI segment. Log p and Log f were identified as the major determinants of permeability, with similar contribution. Total H-bond count was also a significant determinant, followed by polar surface area and M. Leaving out any of the model parameters decreased its predictability. The model was validated against 5 external drugs, with excellent predictability. Notably, the model was able to predict the segmental-dependent permeability of all drugs showing this trend experimentally. Model predictability was better in the high-permeability versus low-permeability range. Overall, our approach of constructing a straightforward in silico model allowed reliable predictions of segmental-dependent intestinal permeability, providing new insights into relative effects of drug-related factors and gastrointestinal environment on permeability.

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Section: In Silico Model Settingsmentioning

confidence: 99%

Segmental-Dependent Intestinal Drug Permeability: Development and Model Validation of In Silico Predictions Guided by In Vivo Permeability Values

Wolk

Marković

Porat

et al. 2019

Journal of Pharmaceutical Sciences

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“…Despite the discovery of very potent and relatively specific MDR1 inhibitors such as valspodar and zosuquidar, pharmacological side effects, pharmacokinetic interactions, toxicity, and/or limited clinical benefit have restricted their use in pharmaceutical formulations (Palmeira et al, 2012;Zakeri-Milani and Valizadeh, 2014). Therefore, natural products (Go et al, 2009;Raju et al, 2011), peptide-coupled compounds (Singh et al, 2014) or surfactants (Akhtar et al, 2017;Beig et al, 2017;Kumari et al, 2017) are currently investigated as MDR1 inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Polysorbate 20 alters the oral bioavailability of etoposide in wild type and mdr1a deficient Sprague-Dawley rats

Al-Ali

Quach²,

Bundgaard

et al. 2018

International Journal of Pharmaceutics

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The aim of the present work was to investigate the ability of nonionic surfactants to increase the oral absorption of the P-glycoprotein substrate etoposide in vitro and in vivo. Intestinal absorption was investigated by studying bidirectional permeability of etoposide across filter-grown Caco-2 and MDCKII MDR1 cell monolayers. The oral absorption of etoposide was investigated in wild type (WT) and mdr1a deficient (KO) Sprague-Dawley rats. In cell cultures, polysorbate 20 (PS20) decreased P-glycoprotein mediated efflux of etoposide. When PS20 and etoposide were co-administered to WT rats, the oral absorption of etoposide increased significantly in the presence of 5 and 25% (v/v) PS20. However, in KO rats, the exposure of etoposide after oral co-administration with 5% PS20 was similar to control. Unexpectedly, co-administration of etoposide with 25% PS20 significantly reduced the absorption fraction of etoposide in mdr1a KO rats. In vitro dialysis studies performed on PS20-containing etoposide solutions suggested that the reduced bioavailability may be due to etoposide retention in PS20 micelles and/or through increased viscosity. In conclusion, PS20 increases oral bioavailability of etoposide through inhibition of P-glycoprotein. However, the use of the excipient may be challenged by etoposide retention at higher concentrations.

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“…21 TPGS is also a P-glycoprotein (P-gp) inhibitor and widely used as an absorption enhancer for improving the oral absorption of insoluble drug. [22][23][24] Our previous research showed that D-α-tocopheryl polyethylene glycol 1000 succinate micelle (TP-PMs) had significantly increased the oral bioavailability of curcumin (Cur); however, the improved transport efficiency of Cur across epithelium by TP-PMs is still limited. 25 Thereafter, to achieve a better transport efficiency and oral absorption of TP-PMs, PepT1-mediated TP-PMs by grafting free amino group onto TP-PMs surface have been proposed, which could specifically recognize PepT1 on epithelium, enhance the affinity of TP-PMs to epithelium, facilitate the transport across intestine, and further increase the oral absorption of TP-PMs.…”

Section: Introductionmentioning

confidence: 99%

Apically targeted oral micelles exhibit highly efficient intestinal uptake and oral absorption

Wang¹,

Wang²,

Liu³

et al. 2018

IJN

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IntroductionPolymeric micelles (PMs) hold promise for improving solubility and oral absorption of poorly soluble drugs. Unfortunately, the oral absorption of PMs is also limited by intestinal epithelium. To improve the oral delivery efficiency of micelles, transporter-mediated micelles could enhance the transport efficiency across the epithelial barrier, and they have attracted more attention.MethodsPeptide transporter 1 (PepT1)-mediated micelles (Val-PMs/Phe-PMs) were designed by grafting valine (or phenylalanine) onto the surface of curcumin (Cur)-loaded-D-α-tocopheryl polyethylene glycol 1000 succinate micelles (TP-PMs). The oral absorption mechanism and oral bioavailability were further investigated in vitro and in vivo.ResultsThe cellular study showed that Val-PMs/Phe-PMs had a high PepT1 affinity, resulting in a higher drug uptake and transcellular transport than TP-PMs. In rats, Val-PMs/Phe-PMs exhibited higher intestinal accumulation in the apical side of the intestinal epithelium than TP-PMs, promoting drug diffusion across epithelial barrier. The oral bioavailability of Cur was significantly improved by Val-PMs/Phe-PMs, which was about 10.50- and 3.40-fold greater than that of Cur-Sol and TP-PMs, respectively.ConclusionPepT-1-mediated micelles, using PepT1 as a target on intestinal epithelium, have unique functions with intestine and prove promising for oral delivery of poorly water-soluble drugs.

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Concomitant solubility-permeability increase: Vitamin E TPGS vs. amorphous solid dispersion as oral delivery systems for etoposide

Cited by 45 publications

References 48 publications

Segmental-Dependent Intestinal Drug Permeability: Development and Model Validation of In Silico Predictions Guided by In Vivo Permeability Values

Segmental-Dependent Intestinal Drug Permeability: Development and Model Validation of In Silico Predictions Guided by In Vivo Permeability Values

Polysorbate 20 alters the oral bioavailability of etoposide in wild type and mdr1a deficient Sprague-Dawley rats

Apically targeted oral micelles exhibit highly efficient intestinal uptake and oral absorption

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