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.