PT  - JOURNAL ARTICLE
AU  - Balani, S K
AU  - Arison, B H
AU  - Mathai, L
AU  - Kauffman, L R
AU  - Miller, R R
AU  - Stearns, R A
AU  - Chen, I W
AU  - Lin, J H
TI  - Metabolites of L-735,524, a potent HIV-1 protease inhibitor, in human urine.
DP  - 1995 Feb 01
TA  - Drug Metabolism and Disposition
PG  - 266--270
VI  - 23
IP  - 2
4099  - http://dmd.aspetjournals.org/content/23/2/266.short
4100  - http://dmd.aspetjournals.org/content/23/2/266.full
SO  - Drug Metab Dispos1995 Feb 01; 23
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.