Metabolism of 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2 (1H)-one (L-696,229), an HIV-1 reverse transcriptase inhibitor, by rat liver slices and in humans.
Healthy subjects were administered single oral doses of 800 mg or 400 mg 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2(1H)-o ne (L-696,229), a nonnucleoside inhibitor of the human immunodeficiency virus-type 1 (HIV-1) reverse transcriptase (RT). Plasma or urine samples were collected over a period of 48 hr. Pooled plasma (0.5-6 hr) and urine (0-24 hr) samples were analyzed by HPLC-UV and HIV-1 RT inhibition assay using poly rC.dG as a template primer. The parent compound and several common metabolites were detected in both samples. The metabolic profiles were also similar to those obtained from a rat liver slice incubation with [3H]L-696,229. The in vitro metabolites were identified by NMR and MS as 5 alpha-hydroxyethyl- (major), 5,6-dihydrodiol-, 6'-hydroxy-, 6-hydroxymethyl-, and 5-vinyl analogs, and a benzoxazole ring hydrolysis product. Most of the significant metabolites in human plasma and urine were found to be identical to the in vitro metabolites, as established by HPLC-UV and MS. Hydrolysis of the plasma and urine with beta-glucuronidase/sulfatase indicated the presence of significant amounts of conjugates of the parent compound and 5 alpha-hydroxyethyl metabolite. Most of the other primary metabolites were also present in conjugated forms, albeit in small quantities. In addition, two secondary metabolites were isolated and identified from the hydrolyzed urine as 5-acetyl-6'-hydroxy- and 5 alpha-hydroxyethyl-6-hydroxymethyl- analogs.(ABSTRACT TRUNCATED AT 250 WORDS)
Balani
S K
SK
Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486.
Kauffman
L R
LR
Arison
B H
BH
Olah
T V
TV
Goldman
M E
ME
Varga
S L
SL
O'Brien
J A
JA
Ramjit
H G
HG
Rooney
C S
CS
Hoffman
J M
JM
D000284:Administration, Oral; D000818:Animals; D001583:Benzoxazoles / Q000493:pharmacokinetics* / Q000494:pharmacology; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011728:Pyridones / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018894:Reverse Transcriptase Inhibitors; D013056:Spectrophotometry, Ultraviolet
D001583:Benzoxazoles; D011728:Pyridones; D018894:Reverse Transcriptase Inhibitors; C076250:L 696229; D054303:HIV Reverse Transcriptase