Improvement of the Bioavailability of Colchicine in Rats by Co-administration of D-α-Tocopherol Polyethylene Glycol 1000 Succinate and a Polyethoxylated Derivative of 12-Hydroxy-Stearic Acid

Abstract

Two surface-active formulation ingredients, a water-soluble derivative of vitamin E (D-alpha-tocopherol polyethylene glycol 1000 succinate, vitamin E-TPGS) as well as a polyethoxylated derivative of 12-hydroxy-stearic acid (Solutol HS 15) were investigated in rats for their potential to increase the oral bioavailability of the p-glycoprotein (p-gp) and cytochrome P450 substrate colchicine. D-alpha-Tocopherol polyethylene glycol 1000 succinate and the polyethoxylated derivative of 12-hydroxy-stearic acid will be referred to as "surfactant 1" and "surfactant 2" in the following. Colchicine was administered to the animals at a dose level of 5 mg/kg in each 10% surfactant containing formulation. A solution of colchicine in isotonic saline was selected as a reference formulation. It was found that the administration of colchicine in the surfactant containing formulations resulted in significantly higher systemic exposures as compared to the aqueous reference vehicle (2-fold increase in AUC in the presence of surfactant 1 and 4-fold increase in AUC in the presence of surfactant 2). The aqueous solubility of colchicine was about 16.7 mg/ml, and the increase in solubility in the presence of 1% surfactant 1 or surfactant 2 to about 20.5 and 18.5 mg/ml was not considered to significantly affect the oral bioavailability. In summary, it was demonstrated that both surfactants are suitable formulation ingredients to improve the systemic exposure of colchicine in the rat. Due to the high aqueous solubility of colchicine the most likely reasons for these findings are inhibition of p-gp and/or metabolism as well as permeability enhancement by interactions of the surfactants with the intestinal membrane.

Interaction of the Main Components from the Traditional Chinese Drug Pair Chaihu-Shaoyao Based on Rat Intestinal Absorption

“…Here, we summarize the possible mechanism of the improved intestinal absorption of paeoniflorin by co-administration with SSA and SSD. Firstly, it has been reported that some surfactants such as Tween-80 can open the tight junction of intestinal epithelial cells to promote the absorption of drugs [ 20 ]. As saikosaponin is a kind of saponin which has surfactant activity, thus it seems that the improved intestinal absorption of paeoniflorin could be attributed to saikosaponin which might increase the intestinal epithelial permeability by opening the tight junction of intestinal epithelial cells.…”

Preparation and evaluation of celecoxib nanosuspensions for bioavailability enhancement

“…29 According to the reports, the administration of colchicine formulation containing TPGS resulted in signicantly higher systemic exposures and 2-fold increase in AUC as compared to the aqueous reference vehicle. 30 TPGS was found to markedly enhance intestinal absorption of berberine chloride (BBR), especially at a concentration of 2.5% achieving around 2.9-and 1.9-fold improvement on C max and AUC 0-36 h of BBR aer oral administration respectively. 31 Pharmaceutical researchers have developed different formulations to increase the solubility and oral bioavailability of CLX.…”

Comment on “ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models”

“…This pH-neutral formulation resulted in the total solvation of the compound. The selected vehicle is used extensively in the pharmaceutical industry to obtain aqueous preparations for safe and efficient oral or parenteral delivery in rodent models (7). Because the effects described by Cramer et al (1,8) were relatively acute, we strove to achieve efficient delivery of fully solubilized compound.…”