Physiologically based pharmacokinetic and pharmacodynamic modeling of an antagonist (SM‐406/AT‐406) of multiple inhibitor of apoptosis proteins (IAPs) in a mouse xenograft model of human breast cancer

The inhibitors of apoptosis proteins (IAPs) are a class of key apoptosis regulators overexpressed or dysregulated in cancer. SM‐406/AT‐406 is a potent and selective small molecule mimetic of Smac that antagonizes the inhibitor of apoptosis proteins (IAPs). A physiologically based pharmacokinetic and pharmacodynamic (PBPK‐PD) model was developed to predict the tissue concentration–time profiles of SM‐406, the related onco‐protein levels in tumor, and the tumor growth inhibition in a mouse model bearing human breast cancer xenograft. In the whole body physiologically based pharmacokinetic (PBPK) model for pharmacokinetics characterization, a well stirred (perfusion rate‐limited) model was used to describe SM‐406 pharmacokinetics in the lung, heart, kidney, intestine, liver and spleen, and a diffusion rate‐limited (permeability limited) model was used for tumor. Pharmacodynamic (PD) models were developed to correlate the SM‐406 concentration in tumor to the cIAP1 degradation, pro‐caspase 8 decrease, CL‐PARP accumulation and tumor growth inhibition. The PBPK‐PD model well described the experimental pharmacokinetic data, the pharmacodynamic biomarker responses and tumor growth. This model may be helpful to predict tumor and plasma SM‐406 concentrations in the clinic. Copyright © 2013 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/100147/1/bdd1850.pd

A Mechanistic Approach to Understanding the Factors Affecting Drug Absorption: A Review of Fundamentals

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97203/1/00970002042006005.pd

Transporter Expression in Liver Tissue from Subjects with Alcoholic or Hepatitis C Cirrhosis Quantified by Targeted Quantitative Proteomics

ABSTRACT Although data are available on the change of expression/activity of drug-metabolizing enzymes in liver cirrhosis patients, corresponding data on transporter protein expression are not available

Examining levels of processing using verbal and pictorial stimuli with the complex trial protocol in a mock theft scenario

The Complex Trial Protocol (CTP) is an EEG-based Concealed Information Test (CIT). Depth of processing influences memorability where deeper processing increases recollection. The CTP's performance as a function of shallow versus deep levels of processing has not been explored. Two experiments were conducted, one with verbal stimuli and the other with their pictorial referents. In both experiments, participants were randomly assigned to three groups, Innocent Control (Control) condition, Guilty Immediate Shallow Processing (Shallow) condition, and Guilty Immediate Deep Processing (Deep) condition. Shallow and Deep participants from both experiments underwent the same mock theft scenario and all three groups were later exposed to either a verbal (N = 41) or pictorial (N = 43) stimulus on a computer monitor. In the word study, no differences in CIT effect were found between any of the groups. Areas under the curve (AUCs) did not differ from chance (.624 and.679 for Shallow and Deep groups respectively). In the image study, the CIT effect for the Shallow and Deep groups differed from the Control one. The AUCs (.755 and.943 for the Shallow and Deep groups respectively) differed significantly from each other. Levels of Processing (LOP) did not appear to have any bearing on CTP performance when words were used as probes but did have an effect when images were used. The findings may hint at some of the limitations of the CTP and fail to replicate similar experiments, especially when words are used as probes, from the late Peter Rosenfeld's laboratory. [Abstract copyright: Copyright © 2023. Published by Elsevier B.V.