title: Preformulation approaches to improve the oral bioavailability of two novel piperidine renin inhibitors in dog.
abstract: Different experimental formulations based on aqueous and oily systems, water miscible solvents, and solid dispersions were investigated for their potential to increase the oral bioavailability (F) of two novel piperidine renin inhibitors (Ro-X1: (R)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]- 5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propan-2-ol; Ro-X2: (R)-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4- methoxy-naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol) in dogs compared to their administration as acidic aqueous solution. The compounds were characterized by a low solubility at pH 7 (Ro-X1: 3 micrograms/ml, Ro-X2: 24 micrograms/ml) and a high lipophilicity (Ro-X1: LogP = 5.7, Ro-X2: LogP = 3.7). For Ro-X1 oil-based vehicles resulted in an improvement in the oral bioavailability compared to the aqueous solution (F = 6 +/- 1.2%) with the best result being achieved with a solution in Capmul (F = 14.6 +/- 3.5%). By contrast, for Ro-X2 the highest bioavailability (F = 27.1 +/- 8.4%) was achieved using an aqueous solution. Computer simulations based on the physicochemical parameters of the compounds only predicted that the fraction of compound absorbed in man should be almost quantitative for Ro-X2 and only about 28% for Ro-X1. These results suggest that other factors such as extensive gut and/or hepatic metabolism as well as exclusion by intestinal transporters such as p-glycoprotein, rather than incomplete solubilization in the gut, are the major reasons for the limited oral bioavailability of both compounds.
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: Ruby
authors.initials: R
authors.lastname: Chou
authors.forename: Michael
authors.initials: M
authors.lastname: Schleimer
authors.forename: Brita
authors.initials: B
authors.lastname: Morgenroth
authors.forename: Manfred
authors.initials: M
authors.lastname: Zell
authors.forename: Thierry
authors.initials: T
authors.lastname: Lavé
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D008297:Male; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics*; D012995:Solubility; D000092502:Renin Inhibitors
chemical_list: D004791:Enzyme Inhibitors; D010880:Piperidines; D000092502:Renin Inhibitors