       Document 0398
 DOCN  M9640398
 TI    Potent and selective inactivation of human liver microsomal cytochrome
       P-450 isoforms by L-754,394, an investigational human immune deficiency
       virus protease inhibitor.
 DT    9604
 AU    Chiba M; Nishime JA; Lin JH; Department of Drug Metabolism, Merck
       Research Laboratories, West; Point, Pennsylvania, USA.
 SO    J Pharmacol Exp Ther. 1995 Dec;275(3):1527-34. Unique Identifier :
       AIDSLINE MED/96108651
 AB    L-754,394,
       N-[2(R)-hydroxy-1(S)-indanyl]-5-[2(S)-(1,1-dimethylethylaminocarb- onyl
       )-4- [(furo[2,3-b]pyridin-5-yl)methyl]piperazin-1-yl]-4(S)-hydroxy-2(R-
       ) - phenylmethylpentanamide, is a potent and specific inhibitor of the
       human immune deficiency virus (HIV) protease. The drug selectively
       inhibited human liver microsomal CYP 3A4-dependent testosterone 6
       beta-hydroxylase and CYP 2D6-dependent bufuralol 1'-hydroxylase
       activities in a time- and concentration-dependent manner in the presence
       of an NADPH-generating system. L-754,394 was found to be a very potent
       inactivator of CYP 3A4. Thus, for testosterone 6 beta-hydroxylase, the
       inactivation kinetic constants, Kl and kinact, were 7.5 microM and 1.62
       min-1, respectively, and the partition ratio (moles product formed per
       moles enzyme inactivated) was approximately 1.35. To a lesser extent,
       L-754,394 also was an inactivator of CYP 2D6, for which the
       corresponding values for Kl, kinact and partition ratio were 32 microM,
       0.18 min-1 and 40, respectively. CYP 3A4 inactivation was reduced
       markedly by ketoconazole, a selective CYP 3A4 inhibitor. Similarly, CYP
       2D6 inactivation also was prevented by quinidine, a specific competitive
       inhibitor of this isoform. However, exogenously added nucleophiles (GSH,
       semicarbazide and N-acetylcysteine) failed to protect against P-450
       inactivation. These results suggest that the inactivation process likely
       is mediated by a reactive metabolite of L-754,394 that alkylates, and
       thereby destroys, the enzyme. Furthermore, this electrophilic
       intermediate may not be released into the medium before the inactivation
       event.
 DE    Cytochrome P-450/*ANTAGONISTS & INHIB  Human  Hydroxylases/*ANTAGONISTS
       & INHIB  HIV Protease Inhibitors/*PHARMACOLOGY  Indans/*PHARMACOLOGY
       Kinetics  Microsomes, Liver/DRUG EFFECTS/*ENZYMOLOGY
       Piperazines/*PHARMACOLOGY  Steroid Hydroxylases/ANTAGONISTS & INHIB
       JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

