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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

In vitro investigation of the hepatic intrinsic clearance of apicidin, a histone deacetylase inhibitor, in mouse, rat, and human, with correction by nonspecific protein binding.

Apicidin is a potent histone deacetylase inhibitor exhibiting broad-spectrum antiprotozoal, antiproliferative, and antiangiogenic activities. This study was conducted to calculate the intrinsic hepatic clearance of apicidin in mouse, rat, and human. The microsomal stability was determined in pooled microsomes of mouse, rat, and human. The V(max) and K(m) were 680.4 ng/min/ mg protein and 10,544.1 ng/ml for mouse, 745.0 ng/min/ mg protein and 24,306.0 ng/ml for rat, and 927.0 ng/min/ mg protein and 62,906.0 ng/ml for human, respectively. The f(u,plasma) was extremely low, 0.369 +/- 0.034% for mouse, 0.376 +/- 0.059% rat, and 1.042 +/- 0.114% human. The unbound fraction of apicidin in microsomes (f(u,mic)) was also low, 1.731 +/- 0.237% for mouse, 0.767 +/- 0.048% for rat, and 5.751 +/- 1.575% for human. The hepatic intrinsic clearance calculated by Michaelis kinetics was further corrected by nonspecific binding to microsomal proteins. The corrected intrinsic clearance of apicidin was 1.9, 8.6, and 284.2 ml/min for mouse, rat, and human, respectively. The allometric correlation was improved when the hepatic intrinsic clearance was corrected by the nonspecific protein binding.[1]


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