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CONCURRENT INDUCTION AND MECHANISM-BASED INACTIVATION OF CYP3A4 BY AN L-VALINAMIDE DERIVATIVE

Preclinical Candidate Optimization, Metabolism and Pharmacokinetics (G.L., R.D., T.J.Y., L.W.) and Clinical Discovery (W.D.F.), Bristol-Myers Squibb Company, Princeton, New Jersey; Preclinical Candidate Optimization, Metabolism and Pharmacokinetics, Bristol-Myers Squibb Company, Wallingford, Connecticut (S.K., M.S.); Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts (F.W.L., L.-S.G.); Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (E.L., S.J., D.G.); Quest Pharmaceutical Services, Inc., Newark, Delaware (J.L., E.S.); InnaPhase Corp., Philadelphia, PA (J.M.B.); and Clinical Pharmacology Consultant, Hockessin, DE (I.H.B.)

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 6ß-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 K_I and k_inact 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.

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