In vitro and in situ evidence for the contribution of Labrasol® and Gelucire 44/14 on transport of cephalexin and cefoperazone by rat intestine

Koga, Kenjiro; Kawashima, Susumu; Murakami, Masahirô

doi:10.1016/s0939-6411(02)00116-9

Cited by 34 publications

(15 citation statements)

References 16 publications

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“…On the other hand, we found an increase in the absorptive transport of Lucifer yellow by Labrasol with relatively high concentration (0.1% (v/v)), and this might be attributed to opening the tight junction of cells caused by Labrasol. However, Koga et al (2002) reported that Labrasol (0.01-0.5% (v/v)) had no significant effect on the intestinal membrane resistance (R m ), an index of loosing the tight junction via a paracellular route. 28) Therefore, further studies are necessary to elucidate the mechanism whereby Labrasol increased the intestinal transport of Lucifer yellow, a typical paracellular marker compound.…”

Section: Discussionmentioning

confidence: 99%

Effects of Labrasol and Other Pharmaceutical Excipients on the Intestinal Transport and Absorption of Rhodamine123, a P-Glycoprotein Substrate, in Rats

Yang

Shen

Katsumi

et al. 2007

Biological & Pharmaceutical Bulletin

102

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P-Glycoprotein (P-gp) is a plasma membrane glycoprotein of about 170 kDa that belongs to the superfamily of ATPbinding cassette (ABC) transporters. P-gp is extensively expressed in tumor cells, liver, intestinal brush border membranes, kidney, brain, and adrenal glands.1) It can actively pump drugs out of cells, thus reducing the oral bioavailability of a wide range of drugs such as digoxin, vinca alkaloids, and b-adrenergic agonists.It has been reported that some P-glycoprotein inhibitors such as verapamil and cyclosporin A could enhance the bioavailability of P-gp substrate drugs.2-4) But it is well known that these drugs themselves have pharmacological activities. Therefore, it is important to find a P-gp inhibitor which does not have pharmacological activities. It has been demonstrated that a number of excipients could inhibit the function of P-gp, thereby increasing the absorption of P-gp substrate drugs. 5) These excipients include polyethylene glycols (PEGs), nonionic surfactants, fatty acids and bile salts. [6][7][8][9][10][11][12][13][14][15][16] It has been reported that several excipients such as Cremophor EL, Tween 80, n-lauryl-b-D-maltopyranoside (LM), Pluronic P85, vitamin E-TPGS, PEGs, sodium caprate and dimethyl-b-cyclodextrin could inhibit the function of Pgp by in vitro and in vivo methods. [6][7][8][9][10][11][12][13][14][15][16] Among these pharmaceutical excipients, Labrasol is one which has been widely used for the solubilization of hydrophobic drugs.17) Labrasol is obtained from coconut oil and has very low toxicity with an LD 50 of 22 g/kg for rats. Recently, it was reported that Labrasol had a strong absorption enhancing effect and that intestinal absorption of various poorly absorbable drugs including gentamicin, insulin and vancomycin was enhanced in its presence. [18][19][20] However, few studies examined the effect of Labrasol on the function of P-gp in the intestine and the intestinal absorption of P-gp substrates. Cornaire et al. (2004) examined the effect of Labrasol on the transport of digoxin by an in vitro everted sac experiment, and reported that 0.5% Labrasol increased the transport of digoxin in this experiment.21) However, they demonstrated that 0.5% Labrasol could increase the lactate dehydrogenase (LDH), and so the increase in digoxin transport might be due to the intestinal membrane damage, and not to the inhibition of P-gp function in the intestine. Furthermore, they did not study the different regional effects of Labrasol on the transport of P-gp substrate and in situ or in vivo intestinal absorption of P-gp substrate with or without Labrasol.In this study, therefore, we studied the effect of Labrasol on the function of P-gp using two different intestinal absorption experiments. We first adopted an in vitro diffusion chamber system using the isolated rat intestinal membrane to evaluate the effects of Labrasol and other pharmaceutical excipients, Gelucire44/14 and Transcutol P on the intestinal transport of rhodamine123, a P-gp substrate. In addition, the intestinal mem...

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Section: Discussionmentioning

confidence: 99%

Effects of Labrasol and Other Pharmaceutical Excipients on the Intestinal Transport and Absorption of Rhodamine123, a P-Glycoprotein Substrate, in Rats

Yang

Shen

Katsumi

et al. 2007

Biological & Pharmaceutical Bulletin

102

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“…Membrane barrier was maintained indicating that labrasol did not change membrane fluidity and authors concluded that labrasol enhanced absorptive transport of PePT1 substrate like cephalexin. [72] Moreover, in a study done on permeation of scutellarin as an MRP2 substrate in Caco-2 cell monolayers, scutellarin concentrations measured in the presence of labrasol were not higher than that in scutellarin standard group. This indicated that labrasol had no effect on MRP2 activity.…”

Section: Labrasolmentioning

confidence: 88%

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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“…Previously, Koga et al (2002) reported that the transport of cephalexin was not affected by the presence of Gelucire 44/14 using the in vitro chamber method. 33) Therefore, our present finding was well correlated with the previous report and suggested that Wellsolve might not affect the function of the carrier-mediated transporter PEPT1.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Wellsolve, a Novel Solubilizing Agent, on the Intestinal Barrier Function and Intestinal Absorption of Griseofulvin in Rats

Hamid

Yang

Gao

et al. 2009

Biological & Pharmaceutical Bulletin

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Recently, molecular weights of many drugs and their candidates have been increasing by the progress of combinatorial chemistry and high throughput screening (HTS). Therefore, it is known that water solubility of these drug candidates tended to decrease because of their large molecular size and high lipophilicity. As drug solubility is one of the most important factors affecting the intestinal drug absorption after oral administration, the poor solubility of these drug candidates is one of the most serious problems to achieve the high bioavailability of these drug candidates.Many strategies have been examined to overcome the low water solubility of drugs and their candidates. These strategies include solid dispersion, salt formulation, emulsion and liposomes and pharmaceutical excipients (solubilizing agents).1) Of these strategies, solubilizing agents have been utilized to improve the solubility of poorly water-soluble drugs and their bioavailability (BA) after oral administration. These solubilizing agents were considered inert substances that would be mainly used as diluents, fillers, binders, lubricants, coatings, solvents, dyes, and in the manufacture of drug products. However, the solubilizing agents may sometimes alter the intestinal membrane integrity and affect the function of transporters including P-glycoprotein (P-gp) and peptide transporter (PEPT1) in the intestine. Indeed, our previous study demonstrated that sodium taurocholate (NaTC), a natural surfactant and a bile salt, could increase the intestinal absorption of phenol red, a poorly absorbable compound in rats and cause the intestinal membrane damage as evaluated by the release amount of protein and phospholipid from the intestinal membranes.2,3) In addition, the intestinal absorption of insulin, gentamicin and other hydrophilic drugs was improved in the presence of Labrasol, one of the typical solubilizing agent. [4][5][6] Furthermore, more recently, we found that NaTC and Labrasol at higher concentrations might alter the intestinal barrier functions and increase the intestinal absorption of 5(6)-carboxyfluorescein (CF) and fluorescein isothiocyanate-labeled dextran with an average molecular weight of 4000 (FD4) in rats. 7)As for the effect of solubilizing agents on the function of transporters, it has been reported that several common excipients could modulate the activity of P-gp, a typical efflux transporter.8) Furthermore, our previous study indicated that Cremophor EL, Tween 80,, polyethyleneglycol (PEGs) and Labrasol also inhibited the function of P-gp in the intestine, thereby reducing the secretory transport of rhodamine123 and other P-gp substrates.9-12) Therefore, it is important to find out a suitable solubilizing agent, which has high potency and no influence on the function of integrity and transporters in the intestine.Based on the background, Wellsolve, a novel solubilizing agent, has recently been developed by Celeste Co., Ltd., although the components of this agent were not disclosed. In the preliminary studies, Wellsolve coul...

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In vitro and in situ evidence for the contribution of Labrasol® and Gelucire 44/14 on transport of cephalexin and cefoperazone by rat intestine

Cited by 34 publications

References 16 publications

Effects of Labrasol and Other Pharmaceutical Excipients on the Intestinal Transport and Absorption of Rhodamine123, a P-Glycoprotein Substrate, in Rats

Effects of Labrasol and Other Pharmaceutical Excipients on the Intestinal Transport and Absorption of Rhodamine123, a P-Glycoprotein Substrate, in Rats

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

The Effect of Wellsolve, a Novel Solubilizing Agent, on the Intestinal Barrier Function and Intestinal Absorption of Griseofulvin in Rats

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