METABOLISM OF THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REVERSE-TRANSCRIPTASE INHIBITOR DELAVIRDINE IN RATS

Delavirdine mesylate (U-90152T) is a highly specific nonnucleoside rev erse transcriptase inhibitor currently under development for the treat ment of AIDS. The excretion, disposition, and metabolism of delavirdin e were investigated in Sprague-Dawley rats after oral administration o f [C-14]delavirdine mesylate at single doses ranging from 10 to 250 mg /kg and multiple doses ranging from 20 to 250 mg/kg/day. Excretion stu dies 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 exten sive. The following metabolites were identified (% of dose in rats giv en 10 and 100 mg/kg, respectively): 6'-hydroxy delavirdine (7.1% and 1 5.6%) 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 conjug ate (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 o f 6'-hydroxy delavirdine generated despyridinyl delavirdine and the py ridine-ring opened MET-14. The metabolic pathway of delavirdine involv ed N-desalkylation, pyridine ring hydroxylation, pyridine ring cleavag e, and amide bond cleavage.