TY - JOUR T1 - CONCURRENT INDUCTION AND MECHANISM-BASED INACTIVATION OF CYP3A4 BY AN <span class="sc">l</span>-VALINAMIDE DERIVATIVE JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1170 LP - 1175 DO - 10.1124/dmd.31.9.1170 VL - 31 IS - 9 AU - Gang Luo AU - Jianrong Lin AU - William D. Fiske AU - Renke Dai AU - Tian J. Yang AU - Sean Kim AU - Michael Sinz AU - Edward LeCluyse AU - Eric Solon AU - James M. Brennan AU - Irma H. Benedek AU - Summer Jolley AU - Darryl Gilbert AU - Lifei Wang AU - Frank W. Lee AU - Liang-Shang Gan Y1 - 2003/09/01 UR - http://dmd.aspetjournals.org/content/31/9/1170.abstract N2 - DPC 681 (N-[(3-fluorophenyl)methyl]glycyl-N-{3-[((3-aminophenyl) sulfonyl)-2-(aminophenyl)amino]-(1S,2S)-2-hydroxy-1-(phenyl-methyl)propyl}-3-methyl-l-valinamide) is a potent peptide-like human immunodeficiency virus protease inhibitor that was evaluated in phase I clinical trials. In primary cultures of hepatocytes, DPC 681 significantly induced the testosterone 6β-hydroxylase activity of rat CYP3A, but not human CYP3A4. Western blot analysis, however, demonstrated a 3-fold increase in expression of CYP3A4 protein by 20 μM DPC 681 in primary cultures of human hepatocytes. Subsequent studies showed that DPC 681 was a potent inhibitor of human CYP3A4 (IC50 = 0.039 μM) and rat CYP3A (IC50 = 1.62 μM). Moreover, DPC 681 was a mechanism-based inactivator of CYP3A4 with KI and kinact of 0.24 μM and 0.22 min-1, respectively. Thus, DPC 681 is both a potent inhibitor and a strong inducer of CYP3A4. Induction of CYP3A4 by DPC 681 was masked in vitro by autoinactivation, similar to the protease inhibitor ritonavir. In pharmacokinetic studies in healthy human volunteers and rats, DPC 681 was found to highly autoinduce its metabolism. Human volunteers dosed with DPC 681 at 600 mg twice daily for 14 days had a 75% decrease in the mean area under the concentration-time curve and a more than 3-fold increase in apparent clearance as compared with that on day 1. Because the primary route of DPC 681 clearance is via CYP3A metabolism, the increased clearance observed in clinical studies is due to induction of human CYP3A4 expression. The American Society for Pharmacology and Experimental Therapeutics ER -