PT  - JOURNAL ARTICLE
AU  - Mayland Chang
AU  - Virendra K. Sood
AU  - Gracella J. Wilson
AU  - David A. Kloosterman
AU  - Phillip E. Sanders
AU  - Michael J. Hauer
AU  - Paul E. Fagerness
TI  - Metabolism of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Inhibitor Delavirdine in Rats
DP  - 1997 Feb 01
TA  - Drug Metabolism and Disposition
PG  - 228--242
VI  - 25
IP  - 2
4099  - http://dmd.aspetjournals.org/content/25/2/228.short
4100  - http://dmd.aspetjournals.org/content/25/2/228.full
SO  - Drug Metab Dispos1997 Feb 01; 25
AB  - 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 itsN-sulfamate, 6′- and 4′-sulfate conjugates (2.9% and 3.9%). Cleavage of the amide bond in delavirdine to giveN-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 involvedN-desalkylation, pyridine ring hydroxylation, pyridine ring cleavage, and amide bond cleavage. The American Society for Pharmacology and Experimental Therapeutics