56 57 58 59 60
Fluorine replacement of a hydrogen atom to block the metabolic site of the drug is widely used in drug design. With the availability of in vitro testing with human liver microsome, S9 fraction and human liver hepatocyctes, it becomes much easier to accurately locate the site of metabolic liability and to install the fluorine atom.
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A significant portion of paclitaxel 61 was found to be excreted through the bile as 6-a-hydroxypaclitaxel 62 in human (58). The hydroxylated metabolite is 30-fold less active than the parent drug. The fluorine analog was designed to overcome this problem. The 6-a-F, CI, Br paclitaxels were found to have similar in vitro and in vivo activities. The human liver S9 incubation of the newer inhibitors did not produce the hydroxylated paclitaxels.
Due to the high electronic negativity of the fluorine atom, it is often used to modulate the physicochemical properties of a molecule. A fluorine atom was often employed to affect the basicity of the amine, thus influencing the bioavailability and metabolic stability. In a recent report, the basicity of the fluorinated molecule was measured to quantify the p and y induction effects of the fluorine atom (59). It was found that the basicity has a dramatic, beneficial influence on oral absorption, but the effect on oral bioavailability could not always be accurately predicted.
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