Solvent-Casted Films to Assist Polymer Selection for Amorphous Solid Dispersions During Preclinical Studies: In-vitro and In-vivo Exploration.

Purpose: The use of two solvent-casted film methods to select optimal polymer compositions for amorphous solid dispersions prepared to support preclinical pharmacokinetic and toxicology studies is described.

Methods: Evaporation of solvent from cover slips by using nitrogen flow, and solvent removal from vials by using rotary evaporation were employed. The films prepared on cover slips were evaluated under the microscope to determine crystallinity.

Bile Salt Homeostasis in Normal and Bsep Gene Knockout Rats with Single and Repeated Doses of Troglitazone.

The interference of bile acid secretion through bile salt export pump (BSEP) inhibition is one of the mechanisms for troglitazone (TGZ)-induced hepatotoxicity. Here, we investigated the impact of single or repeated oral doses of TGZ (200 mg/kg/day, 7 days) on bile acid homoeostasis in wild-type (WT) and Bsep knockout (KO) rats. Following oral doses, plasma exposures of TGZ were not different between WT and KO rats, and were similar on day 1 and day 7.

Biliary excretion of pravastatin and taurocholate in rats with bile salt export pump (Bsep) impairment.

The bile salt export pump (BSEP) is expressed on the canalicular membrane of hepatocytes regulating liver bile salt excretion, and impairment of BSEP function may lead to cholestasis in humans. This study explored drug biliary excretion, as well as serum chemistry, individual bile acid concentrations and liver transporter expressions, in the SAGE Bsep knockout (KO) rat model. It was observed that the Bsep protein in KO rats was decreased to 15% of that in the wild type (WT), as quantified using LC-MS/MS.

Coproporphyrins I and III as Functional Markers of OATP1B Activity: In Vitro and In Vivo Evaluation in Preclinical Species.

Inhibition of organic anion-transporting polypeptide (OATP)1B function can lead to serious clinical drug-drug interactions, thus a thorough evaluation of the potential for this type of interaction must be completed during drug development. Therefore, sensitive and specific biomarkers for OATP function that could be used in conjunction with clinical studies are currently in demand. In the present study, preclinical evaluations were conducted to characterize the suitability of coproporphyrins (CPs) I and III as markers of hepatic OATP functional activity.

Non-basic azolotriazinone MCHR1 antagonists for the treatment of obesity: An empirical brain-exposures-driven candidate selection for in vivo efficacy studies.

Non-basic azolotriazinones were explored using an empirical free brain exposures-driven approach to identify potent MCHR1 antagonists for evaluation in in vivo efficacy studies. An optimized lead from this series, 1j (rMCHR1 Ki=1.8 nM), demonstrated a 6.