title: Improvement of the bioavailability of colchicine in rats by co-administration of D-alpha-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.
authors.affiliation: Pharma Division, DMPK Discovery Support, F. Hoffmann-La Roche Ltd., Basel, Switzerland. beate.bittner@roche.com
authors.forename: Beate
authors.initials: B
authors.lastname: Bittner
authors.forename: Alberto
authors.initials: A
authors.lastname: Guenzi
authors.forename: Pascal
authors.initials: P
authors.lastname: Fullhardt
authors.forename: Gerhard
authors.initials: G
authors.lastname: Zuercher
authors.forename: Roberto Carlos Bravo
authors.initials: RC
authors.lastname: González
authors.forename: Richard Jolyon
authors.initials: RJ
authors.lastname: Mountfield
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D019540:Area Under Curve; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D003078:Colchicine / Q000493:pharmacokinetics*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008297:Male; D011092:Polyethylene Glycols; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013229:Stearic Acids / Q000494:pharmacology*; D013268:Stimulation, Chemical; D013386:Succinates / Q000494:pharmacology*; D013501:Surface-Active Agents / Q000494:pharmacology*; D014810:Vitamin E / Q000031:analogs & derivatives / Q000494:pharmacology*; D024502:alpha-Tocopherol / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000975:Antioxidants; D013229:Stearic Acids; D013386:Succinates; D013501:Surface-Active Agents; D014810:Vitamin E; D011092:Polyethylene Glycols; D003577:Cytochrome P-450 Enzyme System; D024502:alpha-Tocopherol; C014225:tocophersolan; D003078:Colchicine