Metabolism of the human immunodeficiency virus type 1 reverse transcriptase inhibitor delavirdine in rats.
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.
Chang
M
M
Drug Metabolism Research, Pharmacia & Upjohn, Inc., Kalamazoo, MI 49007, USA.
Sood
V K
VK
Wilson
G J
GJ
Kloosterman
D A
DA
Sanders
P E
PE
Hauer
M J
MJ
Fagerness
P E
PE
D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D001646:Bile / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D020008:Delavirdine; D005243:Feces / Q000737:chemistry; D005260:Female; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D007211:Indoles / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D013058:Mass Spectrometry; D010879:Piperazines / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics*
D019380:Anti-HIV Agents; D007211:Indoles; D010879:Piperazines; D018894:Reverse Transcriptase Inhibitors; D020008:Delavirdine