An in vitro examination of the impact of polyethylene glycol 400, pluronic P85, and vitamin E d-a-tocopheryl polyethylene glycol 1000 succinate on P-glycoprotein efflux and enterocyte-based metabolism in excised rat intestine

Abstract

The potential inhibitory effects of 3 excipients (polyethylene glycol [PEG] 400, Pluronic P85, and vitamin E d-a-tocopheryl polyethylene glycol 1000 succinate [TPGS]) on the P-glycoprotein (P-gp) -mediated efflux of digoxin (DIG) and cytochrome P450 3A (CYP3A) -mediated metabolism of verapamil (VRP) have been examined in an in vitro permeability model. Experiments were conducted utilizing rat jejunal tissue mounted in diffusion chambers and included assessment of the serosal to mucosal (s to m) transport of DIG and the formation of norverapamil (NOR) during the mucosal to serosal transport of VRP, as measures of P-gp efflux and CYP3A metabolism, respectively. The presence of PEG at 1%, 5%, and 20% (wt/vol) reduced both the s to m flux of DIG (by 47%, 57%, and 64%, respectively, when compared to control) and the metabolism of VRP (by 54%, 78%, and 100%) in a concentration-dependent manner. P85 (0.1% wt/vol) significantly reduced s to m DIG flux by 47% and inhibited VRP metabolism by 42%. TPGS had insignificant effects on both metabolism and efflux at a concentration of 0.01% (wt/vol). The P-gp inhibitory effects of PEG and P85 were evident regardless of whether the excipient was added to the mucosal side, the serosal side, or both sides of the tissue. The current data suggest that inclusion of PEG and P85 as solubilizing agents during in vitro permeability assessment may have a significant impact on both drug metabolism and efflux processes. These compounds appear to exert their effects on P-gp primarily via direct transporter inhibition - or indirectly, through effects on buffer osmolarity, membrane fluidity, and/or mitochondrial toxicity and subsequent adenosine triphosphate (ATP) depletion.

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

“…[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.…”

A Kinetic Evaluation of the Absorption, Efflux, and Metabolism of Verapamil in the Autoperfused Rat Jejunum

“…The inlet jejunal cannula was connected to a second peristaltic pump (Amersham Biosciences, Inc.), and perfusate was passed through the lumen at 0.6 ml ⅐ min Ϫ1 from a jacketed reservoir that maintained the perfusate at 37°C (Savina et al, 1981 Ϫ , adjusted to pH 6.5 at 37°C (Schanker et al, 1958). In experiments other than control, perfusate contained either the P-gp inhibitor PSC833 (20 M), the CYP3A inhibitor, midazolam (20 M), or the nonselective P-gp/CYP3A inhibitor ketoconazole (50 M) (Johnson et al, 2002). Body temperature was maintained by a heating mat and lamp, and the exposed jejunal segment was covered by saline-soaked gauze and a clear plastic film.…”

Ultra Rapidly Dissolving Repaglinide Nanosized Crystals Prepared via Bottom-Up and Top-Down Approach: Influence of Food on Pharmacokinetics Behavior

“…The highest bioavailability with nanocrystals TD-B, compared to the pure RPG and nanocrystals TD-A can be attributed to the inhibitory effect of adsorbed TPGS on the P-gp efflux transporter (41) as well as on CYP3A4 the main enzyme (21,22) involved in the extensive first-pass metabolism of RPG. TPGS has a low critical micelle concentration (0.02%).…”

“…It improves oral absorption of poorly soluble drugs by increasing solubility as well as by modulating P-gp dependent drug efflux mechanism (17)(18)(19)(20). TPGS also exhibits inhibitory effects on cytochrome P450 3A (CYP3A) (21,22).…”