RT Journal Article SR Electronic T1 Comparison of the Bioactivation Potential of the Antidepressant and Hepatotoxin Nefazodone with Aripiprazole, a Structural Analog and Marketed Drug JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1016 OP 1029 DO 10.1124/dmd.108.020545 VO 36 IS 6 A1 Jonathan N. Bauman A1 Kosea S. Frederick A1 Aarti Sawant A1 Robert L. Walsky A1 Loretta M. Cox A1 Ronald S. Obach A1 Amit S. Kalgutkar YR 2008 UL http://dmd.aspetjournals.org/content/36/6/1016.abstract AB In vitro metabolism/bioactivation of structurally related central nervous system agents nefazodone (hepatotoxin) and aripiprazole (nonhepatotoxin) were undertaken in human liver microsomes in an attempt to understand the differences in toxicological profile. NADPH-supplemented microsomal incubations of nefazodone and glutathione generated conjugates derived from addition of thiol to quinonoid intermediates. Inclusion of cyanide afforded cyano conjugates to iminium ions derived from α-carbon oxidation of the piperazine ring in nefazodone and downstream metabolites. Although the arylpiperazine motif in aripiprazole did not succumb to bioactivation, the dihydroquinolinone group was bioactivated via an intermediate monohydroxy metabolite to a reactive species, which was trapped by glutathione. Studies with synthetic dehydroaripiprazole metabolite revealed an analogous glutathione conjugate with molecular weight 2 Da lower. Based on the proposed structure of the glutathione conjugate(s), a bioactivation sequence involving aromatic ortho-or para-hydroxylation on the quinolinone followed by oxidation to a quinone-imine was proposed. P4503A4 inactivation studies in microsomes indicated that, unlike nefazodone, aripiprazole was not a time- and concentration-dependent inactivator of the enzyme. Overall, these studies reinforce the notion that not all drugs that are bioactivated in vitro elicit a toxicological response in vivo. A likely explanation for the markedly improved safety profile of aripiprazole (versus nefazodone) despite the accompanying bioactivation liability is the vastly improved pharmacokinetics (enhanced oral bioavailability, longer elimination half-life) due to reduced P4503A4-mediated metabolism/bioactivation, which result in a lower daily dose (5–20 mg/day) compared with nefazodone (200–400 mg/day). This attribute probably reduces the total body burden to reactive metabolite exposure and may not exceed a threshold needed for toxicity. The American Society for Pharmacology and Experimental Therapeutics