Adaptive Focused Acoustics™ for Nanosuspensions to Enable Pharmacology Assessment of Poorly Soluble Molecules in Lead Optimization.

In Drug Discovery, pharmacology studies often require benign formulation compositions for safe administration in animal models. Here, we applied Adaptive Focused Acoustics™ (AFA) to a molecular scaffold with challenging physicochemical properties for intraperitoneal administration. Nanosuspensions can be prepared at small scales and provide broad applicability.

Evaluation of the Utility of PXB Chimeric Mice for Predicting Human Liver Partitioning of Hepatic Organic Anion-Transporting Polypeptide Transporter Substrates.

The ability to predict human liver-to-plasma unbound partition coefficient (K) is important to estimate unbound liver concentration for drugs that are substrates of hepatic organic anion-transporting peptide (OATP) transporters with asymmetric distribution into the liver relative to plasma. Herein, we explored the utility of PXB chimeric mice with humanized liver that are highly repopulated with human hepatocytes to predict human hepatic disposition of OATP substrates, including rosuvastatin, pravastatin, pitavastatin, valsartan, and repaglinide. In vitro total uptake clearance and transporter-mediated active uptake clearance in C57 mouse hepatocytes were greater than in PXB chimeric mouse hepatocytes for rosuvastatin, pravastatin, pitavastatin, and valsartan.

Overcoming the Bile Salt-Mediated Formation of Nanocolloids That Inhibit Oral Absorption of VX-985.

This article describes the discovery and characterization of nanocolloidal structures formed between VX-985 (an orally administered inhibitor of hepatitis C virus protease) and the bile salt, sodium taurocholate at concentrations of the latter >4 mM. These complexes (1) distribute narrowly in size around a mean diameter of 260 nm, (2) separate from solution only with ultracentrifugation, and (3) appear to influence the absorption of VX-985 from the intestinal tract in vivo, in rodents and humans. Although the oral bioavailability of suspensions of its solid forms is poor, addition of vitamin E D-alpha-tocopherol polyethylene glycol 1000 succinate to dosing vehicles improves the fraction absorbed of the compound in vivo.

Design and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3-Kinase γ (PI3Kγ) Inhibitors with Potential for the Treatment of Multiple Sclerosis (MS).

The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kγ, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kγ. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis.

Intrasplenic transplantation of isolated adult rat hepatocytes: sex-reversal and/or suppression of the major constituent isoforms of cytochrome P450.

Adult male and female rat hepatocytes were individually transplanted into the spleens of adult male and female rats. The recipients were euthanized at either eight, sixteen, thirty, or forty-five weeks following transplantation, at which time hepatic and splenic levels of liver-specific rat albumin mRNA as well as sex-dependent transcript levels of CYP2C11, -2C12, -2C7, -2A1, and -3A2-which accounts for > 60% of the total concentration of hepatic constituent cytochrome P450-were determined. Whereas the pre-infused hepatocytes expressed their expected cytochrome P450 sexual dimorphisms (female-specific CYP2C12, male-specific CYP3A2, and female-predominant CYP2A1), their post-transplantational competence now reflected the sexual dimorphisms of the recipient (as observed in the host's liver), which supports the concept that the sex-dependent growth hormone circulating profiles are the determinants regulating the expression levels of hepatic cytochrome P450.