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Drug Metabolism Research (M.C., V.K.S., G.J.W., P.E.S., M.J.H.,
P.E.F.) and
Structural, Analytical, and Medicinal Chemistry (D.A.K.),
Pharmacia & Upjohn, Inc.
Delavirdine mesylate (U-90152T) is a highly specific nonnucleoside
reverse transcriptase inhibitor currently under development for the
treatment of AIDS. The excretion, disposition, and metabolism of
delavirdine were investigated in Sprague-Dawley rats after oral
administration of [14C]delavirdine mesylate at single
doses ranging from 10 to 250 mg/kg and multiple doses ranging from 20 to 250 mg/kg/day. Excretion studies showed that feces was the major
route of elimination, delavirdine was well absorbed (>80%) after a 10 mg/kg single dose, and excretion was dose-dependent. The metabolism of
delavirdine in the rat was extensive. The following metabolites were
identified (% of dose in rats given 10 and 100 mg/kg, respectively):
6
-hydroxy delavirdine (7.1% and 15.6%) and its glucuronide (12.2%
and 6.2%) and sulfate (5.5% and 3.2%) conjugates, despyridinyl
delavirdine (12.1% and 11.7%) and its conjugate (13.0% and 11.7%),
desalkyl delavirdine (16.5% and 13.4%), and its
N-sulfamate, 6- and 4-sulfate conjugates (2.9% and
3.9%). Cleavage of the amide bond in delavirdine to give
N-isopropylpyridinepiperazine and indole carboxylic acid constituted a minor pathway. Degradation of 6-hydroxy delavirdine generated despyridinyl delavirdine and the pyridine-ring opened MET-14.
The metabolic pathway of delavirdine involved
N-desalkylation, pyridine ring hydroxylation, pyridine ring
cleavage, and amide bond cleavage.
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