       Document 0552
 DOCN  M9630552
 TI    Characterization of the metabolites of the peptidomimetic human
       immunodeficiency virus type 1 protease inhibitor SK&F 107461 in rats
       using liquid chromatography/mass spectrometry.
 DT    9603
 AU    Potts W; van Horn R; Anderson K; Blake T; Garver E; Joseph G; Dreyer G;
       Shu A; Heys R; Fong KL; Department of Drug Metabolism and
       Pharmacokinetics, SmithKline; Beecham Pharmaceuticals, King of Prussia,
       PA 19406, USA.
 SO    Drug Metab Dispos. 1995 Aug;23(8):799-805. Unique Identifier : AIDSLINE
       MED/96020207
 AB    The metabolic fate of SK&F 107461 [Cbz-Ala-Ala-Phe psi [CHOHCH2]
       Gly-Val-Val-OMe], a potent and specific inhibitor of the protease
       encoded by human immunodeficiency virus type 1, in male Sprague-Dawley
       rats is described. SK&F 107461 is a hexapeptide analog containing a
       hydroxyethylene linkage in place of one of the peptide bonds, and in
       which the amino terminus is blocked with a carbobenzyloxy group and the
       carboxy terminus is modified to a methyl ester. The major metabolites of
       SK&F 107461 found in bile and urine after intravenous administration of
       3H-labeled compound were characterized by LC/MS using either thermospray
       or continuous flow/FAB models of ionization. Approximately 80% of the
       administered radioactivity was recovered in the bile of bile
       duct-exteriorized rats following an intravenous dose.
       Radiochromatographic profiling indicated that SK&F 107461 was subject to
       extensive biotransformation. Structures were determined for three major
       biliary and five major urinary metabolites. Two of the major circulating
       plasma metabolites observed after intravenous bolus administration had
       similar retention times to metabolites that were observed in both bile
       and urine. A pathway for the biotransformation of SK&F 107461 in the rat
       is proposed. The parent molecule underwent two primary modes of
       metabolism. Hydrolysis of the carboxy-terminal ester or hydrolysis of
       the Ala-Ala peptide bond near the amino terminus were the primary
       metabolic events. All of the other metabolites characterized can be
       accounted for by exopeptidase activity subsequent to one or both of
       these primary events. There were no major metabolites observed resulting
       from anything other than hydrolysis of the ester or peptide bonds in the
       parent molecule.
 DE    Amino Acid Sequence  Animal  Antiviral
       Agents/BLOOD/*PHARMACOKINETICS/URINE  Bile/METABOLISM  Biotransformation
       Chromatography, Liquid  HIV Protease
       Inhibitors/BLOOD/*PHARMACOKINETICS/URINE  HIV-1/*ENZYMOLOGY  Male
       Molecular Sequence Data  Oligopeptides/BLOOD/*PHARMACOKINETICS/URINE
       Rats  Rats, Sprague-Dawley  Spectrum Analysis, Mass  JOURNAL ARTICLE

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

