Enhanced intestinal absorption of etoposide by self-microemulsifying drug delivery systems: Roles of P-glycoprotein and cytochrome P450 3A inhibition

Zhao, Gang; Huang, Jiangeng; Xue, Kewen; Si, Luqin; Gao, Li

doi:10.1016/j.ejps.2013.08.016

Cited by 61 publications

(42 citation statements)

References 38 publications

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“…13,32,42,43 However, the latter mechanism seems unlikely to play a role in modulating the bioavailability of RES since RES is not a substrate of P-glycoprotein, and the glucuronidation, rather than cytochrome P450-mediated metabolisms, represents the main impediments to the bioavailability. 10,28 Solubilization is often considered as one of main hurdles for the oral bioavailability of RES, 9,10 although an earlier study suggested that increasing the aqueous solubility by ∼59500-fold did not significantly improve the oral absorption.…”

Section: ■ Discussionmentioning

confidence: 96%

Involvement of the Inhibition of Intestinal Glucuronidation in Enhancing the Oral Bioavailability of Resveratrol by Labrasol Containing Nanoemulsions

Zhou

Yang

et al. 2015

Mol. Pharmaceutics

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Nanoemulsions have been developed for the oral delivery of poorly bioavailable phenolic compounds that are sensitive to intestinal glucuronidation. However, little is known about the contribution of UDP-glucuronosyltransferase (UGT) inhibitory excipients in nanoemulsions toward the inhibition of intestinal glucuronidation and the consequent enhanced bioavailability. In this study, Labrasol but not poloxamer 188 (F68) was found to inhibit the glucuronidation of resveratrol (RES), a model phenolic compound, in an inhibition assay with rat microsomes. Subsequently, two nanoemulsions, Lab-N and F68-N, were prepared with similar particle size distribution, zeta potentials, and entrapment efficiency by coemulsifying with Labrasol or F68, respectively. Although Lab-N exhibited inferior or comparable profiles of in vitro release, cellular uptake in Caco-2 cells, and lymphatic transport in rats to F68-N, the in vitro absorption study with everted sacs suggested that Labrasol containing formulations significantly and dose-dependently increased the transport of RES relative to free RES or F68-N by decreasing the amount of permeated metabolite, RES-3-glucuronide (RES-G). The in vivo pharmacokinetic experiments indicated that Lab-N exhibited increments in the maximum plasma concentration and the bioavailability of RES by 1098% and 560%, respectively, and significant decreases in those of RES-G, compared to F68-N. The overall results demonstrated that the improved oral bioavailability of RES by Lab-N was mainly attributable to the inhibition of intestinal glucuronidation by the presence of UGT inhibitory excipient.

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Section: ■ Discussionmentioning

confidence: 96%

Involvement of the Inhibition of Intestinal Glucuronidation in Enhancing the Oral Bioavailability of Resveratrol by Labrasol Containing Nanoemulsions

Zhou

Yang

et al. 2015

Mol. Pharmaceutics

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“…The percentage of silibinin in silymarin was 45.0% according to the certificate of analysis provided by the vendor. DAPI (4′,6-diamidino-2-phenylindole) was supplied by Invitrogen (Carlsbad, CA, USA).…”

Section: Materials and Methods Materialsmentioning

confidence: 99%

“…Some lipids and surfactants in self-emulsifying systems, such as monoglycerides, Cremophor, and polysorbates, are known to inhibit P-glycoprotein and cytochrome P450. 9,45 Most of the transporters and efflux pumps are present in the proximal small intestine, which is bypassed by RYGB. 30 Inhibition of P-glycoprotein and cytochrome P450 by SNEDDS for enhanced availability may be ruled out as the predominant mechanism.…”

mentioning

confidence: 99%

Self-nanoemulsifying drug delivery systems ameliorate the oral delivery of silymarin in rats with Roux-en-Y gastric bypass surgery

Chen

Chang

Shih

et al. 2015

IJN

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Roux-en-Y gastric bypass (RYGB) is a popular surgery to reduce the body weight of obese patients. Although food intake is restricted by RYGB, drug absorption is also decreased. The purpose of this study was to develop novel self-nanoemulsifying drug delivery systems (SNEDDS) for enhancing the oral delivery of silymarin, which has poor water solubility. The SNEDDS were characterized by size, zeta potential, droplet number, and morphology. A technique of RYGB was performed in Sprague-Dawley rats. SNEDDS were administered at a silymarin dose of 600 mg/kg in normal and RYGB rats for comparison with silymarin aqueous suspension and polyethylene glycol (PEG) 400 solution. Plasma silibinin, the main active ingredient in silymarin, was chosen for estimating the pharmacokinetic parameters. SNEDDS diluted in simulated gastric fluid exhibited a droplet size of 190 nm with a spherical shape. The nanocarriers promoted silibinin availability via oral ingestion in RYGB rats by 2.5-fold and 1.5-fold compared to the suspension and PEG 400 solution, respectively. A significant double-peak concentration of silibinin was detected for RYGB rats receiving SNEDDS. Fluorescence imaging showed a deeper and broader penetration of Nile red, the fluorescence dye, into the gastrointestinal mucosa from SNEDDS than from PEG 400 solution. Histological examination showed that SNEDDS caused more minor inflammation at the gastrointestinal membrane as compared with that caused by PEG 400 solution, indicating a shielding of direct silymarin contact with the mucosa by the nanodroplets. SNEDDS generally showed low-level or negligible irritation in the gastrointestinal tract. Silymarin-loaded SNEDDS were successfully developed to improve the dissolution, permeability, and oral bioavailability of silymarin. To the best of our knowledge, this is the first investigation reporting the usefulness of SNEDDS for improving drug malabsorption elicited by gastric bypass surgery.

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“…For few excipients, their crucial mechanisms have not yet been fully revealed but in the presence of these excipients, the activity of transporters gets altered, on an especially functional level. However, more clinical data are necessary to address in vivo correlation of these [65] Cremophor ® EL P-gp Microemulsion Docetaxel [29] Labrasol Not mentioned Microemulsion Gentamicin [71] Oleic acid BCRP Emulsion Mitoxantrone [75] N-octyl-O-sulfate chitosan P-gp Micelles Paclitaxel [62] Peceol ® P-gp Micelles Amphotericin B [80] Solutol ® HS15 P-gp Lipid nanocapsule Paclitaxel [52] β-cyclodextrin P-gp Inclusion complex Berberine hydrochloride [91] Methyl-β-cyclodextrin P-gp Inclusion complex Saquinavir [94] TPGS, Cremophor ® EL P-gp SMEDDS Tacrolimus [35] Cremophor EL P-gp SMEDDS Irinotecan [95] Polysorbate 80/Cremophor EL/Cremophor RH40 P-gp SMEDDS Etoposide [96] DPPC, DPPE P-gp Liposomes Epirubicin [84] TPGS 1000 P-gp Soft gelatin capsule Amprenavir [41] BCRP: Breast cancer resistant protein, SMEDDS: Self-microemulsifying drug delivery system, P-gp: Permeability glycoprotein, TPGS: Tocopheryl-polyethyleneglycol, DPPC: Dipalmotylphosphotidyl choline, DPPE: Dipalmitoylphosphatidylethanolamine interaction activities for few excipients. Result of cellular level studies varies with the cell line model used and the lack of repeatability in results, and there is a need of more accurate cellular studies.…”

Section: Toxicity Profile Of the Pharmaceutical Excipientsmentioning

confidence: 99%

Influence of excipients on drug absorption via modulation of intestinal transporters activity

Thakkar¹,

Desai²

2015

Asian J Pharm

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O ne of the major factors affecting oral drug bioavailability is the activity of intestinal transport proteins, particularly for the drugs that undergo absorption by active transport mechanism. Many of the active pharmacological agents and the excipients used in their formulation are reported to modulate the activity of these transporters thereby either enhancing or decreasing the drug absorption and its systemic availability. These excipients are considered pharmacologically "inert" and have been used since years in pharmaceutical formulations. Appreciable interest is developing on the data demonstrating the role of excipients in altering the drug absorption across the intestine. Careful selection of the excipients thus is very important. A correctly chosen excipient can enhance the drug bioavailability and thus its therapeutic efficacy without increasing its dose. For locally acting drugs having systemic side effects, a proper excipient could lead to a decrease in its systemic absorption, thus reducing its side effects. This review focuses on the current findings of the excipients identified to modulate the activity of transporters, their mechanism of modulating the transporter's activity and various formulation strategies using these excipients to enhance drug absorption.

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Enhanced intestinal absorption of etoposide by self-microemulsifying drug delivery systems: Roles of P-glycoprotein and cytochrome P450 3A inhibition

Cited by 61 publications

References 38 publications

Involvement of the Inhibition of Intestinal Glucuronidation in Enhancing the Oral Bioavailability of Resveratrol by Labrasol Containing Nanoemulsions

Involvement of the Inhibition of Intestinal Glucuronidation in Enhancing the Oral Bioavailability of Resveratrol by Labrasol Containing Nanoemulsions

Self-nanoemulsifying drug delivery systems ameliorate the oral delivery of silymarin in rats with Roux-en-Y gastric bypass surgery

Influence of excipients on drug absorption via modulation of intestinal transporters activity

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