RT Journal Article SR Electronic T1 1-Aminobenzotriazole, a Known Cytochrome P450 Inhibitor, Is a Substrate and Inhibitor of N-Acetyltransferase JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1674 OP 1679 DO 10.1124/dmd.111.039834 VO 39 IS 9 A1 Q. Sun A1 T. W. Harper A1 E. A. Dierks A1 L. Zhang A1 S. Chang A1 A. D. Rodrigues A1 P. Marathe YR 2011 UL http://dmd.aspetjournals.org/content/39/9/1674.abstract AB 1-Aminobenzotriazole (ABT) has been used widely as a nonselective in vitro and in vivo inhibitor of cytochrome P450 enzymes. To date, however, it has not been evaluated as an inhibitor of UDP-glucuronosyltransferase (UGT), sulfotransferase (SULT), and N-acetyltransferase (NAT). In the present study, ABT was shown not to inhibit UGT and SULT activity (acetaminophen and 7-hydroxycoumarin as substrates) in rat liver microsomes and rat liver 9000g supernatant fraction (RLS9), respectively. However, it did inhibit the RLS9-catalyzed N-acetylation of procainamide (IC50 ∼ 30 μM), and no preincubation time dependence was evident. In agreement, oral ABT (100 mg/kg, 2 h predose) decreased the clearance of intravenous procainamide (45%) in rats, accompanied by a decreased N-acetylprocainamide-to-procainamide ratio in urine (0.74 versus 0.21) and plasma (area under the curve ratio 0.59 versus 0.11). Additional studies with human forms of NAT (hNAT1 and hNAT2) revealed that ABT is a more potent inhibitor of hNAT2 compared with hNAT1 (IC50 158 μM versus > 1 mM). Consistent with the IC50 estimate, formal inhibition studies revealed that inhibition of hNAT2 was competitive with an inhibition constant of 67 μM. In accordance with the competitive inhibition, ABT was shown to undergo N-acetylation in the presence of both human NAT forms, with hNAT1 exhibiting less activity under the same assay conditions (∼40% of hNAT2). In summary, the results described herein indicate that ABT is a substrate and inhibitor of NAT. Such an interaction should be considered when using ABT as a nonselective inhibitor of P450, especially when NAT-dependent metabolism is also involved.