Minipig and Human Metabolism of Aldehyde Oxidase Substrates: In Vitro-In Vivo Comparisons.

The importance of aldehyde oxidase (AOX) is becoming increasingly recognized in the prediction of human pharmacokinetic parameters from animal data. The objectives of these studies were to ascertain whether an in vitro-in vivo correlation existed in the clearance and metabolic pathways of AOX substrates and to establish whether the minipig represented an appropriate non-rodent model for man in the pre-clinical development of drugs metabolized by AOX. Using the AOX substrates carbazeran, 6-deoxypenciclovir and zaleplon, clearance was estimated from in vitro depletion experiments with minipig and human liver cytosol and microsomes and scaled before comparison with data generated in parallel in vivo studies in minipigs. In vitro and in vivo metabolic pathways were characterized by LC-MS/MS. Scaling of in vitro metabolism data to predict in vivo clearance underestimated in vivo values, although the rank order of clearance for the three compounds was preserved. Prediction of human in vivo clearance from scaled minipig in vivo data produced results which correlated well with published clinical values. Overall, this study is the first to compare minipig in vitro metabolism data with in vivo pharmacokinetic data for compounds metabolized by AOX and provides a scientific rationale for the selection of this species as a model for humans in the development of drugs which are substrates of AOX.

An experimental test of stimulus estimation theory: danger and safety with snake phobic stimuli.

The stimulus estimation model (Taylor & Rachman, 1994) asserts that fear overprediction stems from: (a) overprediction of the danger elements of a phobic stimulus, and (b) underprediction of existing safety resources. Using a 2x2 factorial design, with danger (high vs low) and safety (high vs low) as between-subjects variables, an experimental test of the model was conducted with 25 snake-fearful participants per condition. The four experimental conditions were matched on initial levels of snake fearfulness, as assessed by the Snake Questionnaire (SNAQ). For the 51 participants who demonstrated overprediction of fear, high danger led to reliably more fear overprediction than low danger; and low safety led to reliably more fear overprediction than high safety. The interaction between danger and safety was not statistically significant. The results offer the first convincing experimental support for the stimulus estimation model of fear overprediction.

Structure of a Cys25-->Ser mutant of human cathepsin S.

Cathepsin S (EC 3.4.22.27), a cysteine proteinase of the papain superfamily, plays a critical role in the generation of a major histocompatibility complex (MHC) class II restricted T-cell response by antigen-presenting cells. Therefore, selective inhibition of this enzyme may be useful in modulating class II restricted T-cell responses in immune-related disorders such as rheumatoid arthritis, multiple sclerosis and extrinsic asthma. The three-dimensional structure at 2.2 A resolution of the active-site Cys25-->Ser mutant presented here in an unliganded state provides further insight useful for the design of selective enzyme inhibitors.