title: The absorption, distribution, metabolism and elimination of bevirimat in rats.
abstract: Bevirimat is the first drug in the class of maturation inhibitors, which treat HIV infection by disrupting the activity of HIV protease enzyme with a mechanism of action distinct from that of conventional protease inhibitors. The absorption, distribution, metabolism and elimination characteristics of single intravenous (25 mg/kg) and oral (25 mg/kg and 600 mg/kg) doses of 14C-bevirimat were studied in male Sprague Dawley and Long Evans rats. Pharmacokinetic and mass-balance studies revealed that bevirimat was cleared rapidly (within 12-24 h) after dosing, although plasma radioactivity was quantifiable up to 168 h. Radioactive metabolites of bevirimat were responsible for approximately 60-80% of plasma radioactivity. Systemically available bevirimat was predominantly (97%) excreted via bile in the faeces, with <or=1% of the dose excreted renally. Less than 0.1% of the dose was excreted in expired air. Quantitative whole-body autoradiography detected high quantities of radioactivity in the bile and liver soon after intravenous dose administration, and evidence of biliary excretion present during the 8 h following oral dosing. Oral bioavailability for the 25 mg/kg dose of bevirimat was estimated at 22-24% by pharmacokinetic and mass-balance methods, with bioavailability decreasing disproportionately with increasing dose for the 600 mg/kg group.
authors.affiliation: Panacos Pharmaceuticals, Inc., 209 Perry Parkway, Unit 7, Gaithersburg MD 20877, USA. pbullock@panacos.com
authors.forename: Peter
authors.initials: P
authors.lastname: Bullock
authors.forename: Douglas
authors.initials: D
authors.lastname: Larsen
authors.forename: Randy
authors.initials: R
authors.lastname: Press
authors.forename: Tod
authors.initials: T
authors.lastname: Wehrman
authors.forename: David E
authors.initials: DE
authors.lastname: Martin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001345:Autoradiography; D001646:Bile / Q000378:metabolism; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D005243:Feces / Q000737:chemistry; D015658:HIV Infections / Q000188:drug therapy; D007275:Injections, Intravenous; D008297:Male; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D013386:Succinates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014315:Triterpenes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D053978:Pentacyclic Triterpenes
chemical_list: D019380:Anti-HIV Agents; D013386:Succinates; D014315:Triterpenes; C479935:bevirimat; D053978:Pentacyclic Triterpenes