RT Journal Article
SR Electronic
T1 Characterization of the metabolites of the peptidomimetic human immunodeficiency virus type 1 protease inhibitor SK&F 107461 in rats using liquid chromatography/mass spectrometry.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 799
OP 805
VO 23
IS 8
A1 W Potts
A1 R van Horn
A1 K Anderson
A1 T Blake
A1 E Garver
A1 G Joseph
A1 G Dreyer
A1 A Shu
A1 R Heys
A1 K L Fong
YR 1995
UL http://dmd.aspetjournals.org/content/23/8/799.abstract
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.