RT Journal Article
SR Electronic
T1 Metabolites of L-735,524, a potent HIV-1 protease inhibitor, in human urine.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 266
OP 270
VO 23
IS 2
A1 Balani, S K
A1 Arison, B H
A1 Mathai, L
A1 Kauffman, L R
A1 Miller, R R
A1 Stearns, R A
A1 Chen, I W
A1 Lin, J H
YR 1995
UL http://dmd.aspetjournals.org/content/23/2/266.abstract
AB L-735,524, N-[2(R)-hydroxy-1(S)-indanyl]-5-(2(S)-(1,1- dimethylethylaminocarbonyl)-4-[(pyridin-3-yl)methyl]piperazin++ +-1-yl)-4(S)- hydroxy-2(R)-phenylmethylpentanamide, is a potent and specific inhibitor of the human immunodeficiency virus type 1 protease and is undergoing clinical evaluation. In an initial clinical study, noninfected male volunteers were administered single, 1000 mg oral doses of nonlabeled compound. Urine samples were collected over a period of 48 hr. Metabolic profile of the urine was determined by HPLC-UV comparison with that from a human liver slice incubation of radiolabeled L-735,524. Seven significant metabolites were isolated from pooled human urine, and were characterized by NMR, MS, and/or chromatographic comparisons with authentic standards. The major metabolic pathways were identified as: a) glucuronidation at the pyridine nitrogen to yield a quaternized ammonium conjugate, b) pyridine N-oxidation, c) para-hydroxylation of the phenylmethyl group, d) 3'-hydroxylation of the indan, and e) N-depyridomethylation. A minor product was identified as 2',3'-trans-dihydroxyindan analog. Urinary excretion of L-735,524 and its metabolites represented a minor pathway of elimination. The intact parent compound seemed to be the major component in the urine, whereas the level of each metabolite was relatively low.