Preformulation Approaches to Improve the Oral Bioavailability of Two Novel Piperidine Renin Inhibitors in Dog
| Autor: | Manfred Zell, Beate Bittner, Michael Schleimer, Thierry Lavé, Brita Morgenroth, Ruby C. Chou |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Chemical Phenomena Chemistry Pharmaceutical Biological Availability Intestinal absorption chemistry.chemical_compound Dogs Piperidines Pharmacokinetics Oral administration Renin Drug Discovery Animals Organic chemistry Enzyme Inhibitors Solubility Chromatography High Pressure Liquid Aqueous solution Chromatography Chemistry Physical Chemistry Bioavailability Intestinal Absorption Area Under Curve Lipophilicity Piperidine |
| Zdroj: | Arzneimittelforschung. 52:593-599 |
| ISSN: | 1616-7066 0004-4172 |
| DOI: | 10.1055/s-0031-1299936 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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