title: Metabolism of the human immunodeficiency virus type 1 reverse transcriptase inhibitor delavirdine in rats.
abstract: 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.
authors.affiliation: Drug Metabolism Research, Pharmacia & Upjohn, Inc., Kalamazoo, MI 49007, USA.
authors.forename: M
authors.initials: M
authors.lastname: Chang
authors.forename: V K
authors.initials: VK
authors.lastname: Sood
authors.forename: G J
authors.initials: GJ
authors.lastname: Wilson
authors.forename: D A
authors.initials: DA
authors.lastname: Kloosterman
authors.forename: P E
authors.initials: PE
authors.lastname: Sanders
authors.forename: M J
authors.initials: MJ
authors.lastname: Hauer
authors.forename: P E
authors.initials: PE
authors.lastname: Fagerness
mesh_terms: 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*
chemical_list: D019380:Anti-HIV Agents; D007211:Indoles; D010879:Piperazines; D018894:Reverse Transcriptase Inhibitors; D020008:Delavirdine