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: M Chang, V K Sood, G J Wilson, D A Kloosterman, P E Sanders, M J Hauer, P E Fagerness
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 25 Issue 2 Pg. 228-42 (Feb 1997) ISSN: 0090-9556 [Print] United States
• PMID: 9029054 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Anti-HIV Agents
• Indoles
• Piperazines
• Reverse Transcriptase Inhibitors
• Delavirdine

Topics

• Administration, Oral
• Animals
• Anti-HIV Agents (pharmacokinetics)
• Bile (chemistry)
• Chromatography, High Pressure Liquid
• Delavirdine
• Feces (chemistry)
• Female
• HIV-1 (drug effects, enzymology)
• Indoles (pharmacokinetics, urine)
• Male
• Mass Spectrometry
• Piperazines (pharmacokinetics, urine)
• Rats
• Rats, Sprague-Dawley
• Reverse Transcriptase Inhibitors (pharmacokinetics)