46 research outputs found
Self-emulsifying therapeutic system: a potential approach for delivery of lipophilic drugs
Effects of Single Dose Rifampin on the Pharmacokinetics of Fluvastatin in Healthy Volunteers
Effect of the injection site on the bioavailability of amoxycillin trihydrate in dairy cows
Drug Absorption Interactions Between Oral Targeted Anticancer Agents and PPIs: Is pH-Dependent Solubility the Achilles Heel of Targeted Therapy?
Pharmacokinetics and metabolism of 2-aminothiazoles with antiprion activity in mice
Purpose: To discover drugs lowering PrP in prion-infected cultured neuronal cells that achieve high concentrations in brain to test in mouse models of prion disease and then treat people with these fatal diseases. Methods: We tested 2-AMT analogs for EC and PK after a 40 mg/kg single dose and 40-210 mg/kg/day doses for 3 days. We calculated plasma and brain AUC, ratio of AUC/EC after dosing. We reasoned that compounds with high AUC/EC ratios should be good candidates going forward. Results: We evaluated 27 2-AMTs in single-dose and 10 in 3-day PK studies, of which IND24 and IND81 were selected for testing in mouse models of prion disease. They had high concentrations in brain after oral dosing. Absolute bioavailability ranged from 27-40%. AUC/EC ratios after 3 days were >100 (total) and 48-113 (unbound). Stability in liver microsomes ranged from 30->60 min. Ring hydroxylated metabolites were observed in microsomes. Neither was a substrate for the MDR1 transporter. Conclusions: IND24 and IND81 are active in vitro and show high AUC/EC ratios (total and unbound) in plasma and brain. These will be evaluated in mouse models of prion disease