ABSTRACT:In previous studies, it was shown that liver microsomes from rabbit, rat, pig, and human are involved in the reduction of N-hydroxylated amidines, guanidines, and amidinohydrazones of various drugs and model compounds (Drug Metab Rev 34: 565-579). One responsible enzyme system, the microsomal benzamidoxime reductase, consisting of cytochrome b 5 , its reductase, and a cytochrome P450 isoenzyme, was isolated from pig liver microsomes (J Biol Chem 272:19615-19620). Further investigations followed to establish whether such enzyme systems are also present in microsomes of other organs such as brain, lung, and intestine. In addition, the mitochondrial reduction in human and porcine liver and kidney preparations was studied. . Interestingly, preparations of all tested organs were capable of reducing the three compounds. The highest specific rates were found in kidney followed by liver, brain, lung, and intestine, and usually the mitochondrial reduction rates were superior. From the determined characteristics, similarities between the enzyme systems in the different organs and organelles were detected. Furthermore, properties of the benzamidoxime reductase located in the outer membrane of pig liver mitochondria were studied. In summary, these results demonstrate that in addition to the microsomal reduction, mitochondria are involved to a great extent in the activation of amidoxime prodrugs. The importance of extrahepatic metabolism in the reduction of N-hydroxylated prodrugs is demonstrated.Numerous drugs and drug candidates contain strongly basic functional groups, such as guanidines, amidinohydrazones, and amidines. Because of their strong basicity, they are protonated under physiological conditions and usually not absorbed in the gastrointestinal tract. In our laboratory, a prodrug principle was developed in particular for amidines by N-hydroxylating this functional group to the corresponding amidoximes, substances with a less basic functional group. Consequently, they are not protonated under physiological conditions and can easily be absorbed as free bases. By creating these prodrugs of the active principle, the oral bioavailability of amidines can be increased. Thus amidoximes and similar functional groups can be used as prodrugs for amidines and related groups.The prodrug principle was developed for pentamidine (Clement, 1993) and was then applied to other amidines such as trypanocidal compounds (Zhou et al., 2004), glycoprotein IIIa/IIb receptor antagonists, such as sibrafiban (Weller et al., 1996), and the thrombin inhibitor ximelagatran, which was recently approved and is the first orally available direct thrombin inhibitor on the market (Gustafsson et al., 2001). Benzamidoxime is a model compound for such amidoxime prodrugs, which are known to be reduced by liver microsomes from different species as well as by the purified enzyme system from pig liver (Clement et al., 1997). Therefore, the reduction of this substrate and its HPLC analysis can be taken as a reliable activity assay (Fig. 1).Sibrafiban...
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