TY - JOUR T1 - <em>N</em>-Acetyltransferase 2 Genotype-Dependent <em>N</em>-Acetylation of Hydralazine in Human Hepatocytes JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1276 LP - 1281 DO - 10.1124/dmd.117.078543 VL - 45 IS - 12 AU - Cecily E. Allen AU - Mark A. Doll AU - David W. Hein Y1 - 2017/12/01 UR - http://dmd.aspetjournals.org/content/45/12/1276.abstract N2 - Hydralazine is used in the treatment of essential hypertension and is under investigation for epigenetic therapy in the treatment of neoplastic and renal diseases. N-acetyltransferase (NAT) 2 exhibits a common genetic polymorphism in human populations. After recombinant expression in yeast, human NAT2 exhibited an apparent Lineweaver-Burk constant (K­m) value (20.1 ± 8.8 μM) for hydralazine over 20-fold lower than the apparent K­m value (456 ± 57 μM) for recombinant human NAT1 (P = 0.0016). The apparent Vmax value for recombinant human NAT1 (72.2 ± 17.9 nmol acetylated/min/mg protein) was significantly (P = 0.0245) lower than recombinant human NAT2 (153 ± 15 nmol acetylated/min/mg protein), reflecting 50-fold higher clearance for recombinant human NAT2. Hydralazine NAT activities exhibited a robust acetylator gene dose response in cryopreserved human hepatocytes both in vitro and in situ. Hydralazine NAT activities in vitro differed significantly with respect to NAT2 genotype at 1000 (P = 0.0319), 100 (P = 0.002), and 10 μM hydralazine (P = 0.0029). Hydralazine NAT activities differed significantly (P &lt; 0.001) among slow acetylator hepatocytes, (NAT2*5B/*5B &gt; NAT2*5B/*6A &gt; NAT2*6A/*6A). The in situ hydralazine N-acetylation rates differed significantly with respect to NAT2 genotype after incubation with 10 (P = 0.002) or 100 µM (P = 0.0015) hydralazine and were higher after incubation with 100 μM (10-fold) than with 10 μM (4.5-fold) hydralazine. Our results clearly document NAT2 genotype–dependent N-acetylation of hydralazine in human hepatocytes, suggesting that hydralazine efficacy and safety could be improved by NAT2 genotype–dependent dosing strategies. ER -