title: Concurrent induction and mechanism-based inactivation of CYP3A4 by an L-valinamide derivative.
abstract: 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 6beta-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 microM DPC 681 in primary cultures of human hepatocytes. Subsequent studies showed that DPC 681 was a potent inhibitor of human CYP3A4 (IC50 = 0.039 microM) and rat CYP3A (IC50 = 1.62 microM). Moreover, DPC 681 was a mechanism-based inactivator of CYP3A4 with KI and kinact of 0.24 microM 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.
authors.affiliation: Preclinical Candidate Optimization, Metabolism and Pharmacokinetics, Princeton, New Jersey 08534, USA. gang.luo@bms.com
authors.forename: Gang
authors.initials: G
authors.lastname: Luo
authors.forename: Jianrong
authors.initials: J
authors.lastname: Lin
authors.forename: William D
authors.initials: WD
authors.lastname: Fiske
authors.forename: Renke
authors.initials: R
authors.lastname: Dai
authors.forename: Tian J
authors.initials: TJ
authors.lastname: Yang
authors.forename: Sean
authors.initials: S
authors.lastname: Kim
authors.forename: Michael
authors.initials: M
authors.lastname: Sinz
authors.forename: Edward
authors.initials: E
authors.lastname: LeCluyse
authors.forename: Eric
authors.initials: E
authors.lastname: Solon
authors.forename: James M
authors.initials: JM
authors.lastname: Brennan
authors.forename: Irma H
authors.initials: IH
authors.lastname: Benedek
authors.forename: Summer
authors.initials: S
authors.lastname: Jolley
authors.forename: Darryl
authors.initials: D
authors.lastname: Gilbert
authors.forename: Lifei
authors.initials: L
authors.lastname: Wang
authors.forename: Frank W
authors.initials: FW
authors.lastname: Lee
authors.forename: Liang-Shang
authors.initials: LS
authors.lastname: Gan
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004790:Enzyme Induction; D005260:Female; D017320:HIV Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012293:Rifampin / Q000494:pharmacology; D019438:Ritonavir / Q000494:pharmacology; D013250:Steroid Hydroxylases / Q000096:biosynthesis; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; C444448:DPC 681; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C022657:steroid hormone 6-beta-hydroxylase; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating; D019438:Ritonavir; D012293:Rifampin; D004121:Dimethyl Sulfoxide