The absorption, distribution, metabolism and elimination of bevirimat in rats.
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.
Bullock
Peter
P
Panacos Pharmaceuticals, Inc., 209 Perry Parkway, Unit 7, Gaithersburg MD 20877, USA. pbullock@panacos.com
Larsen
Douglas
D
Press
Randy
R
Wehrman
Tod
T
Martin
David E
DE
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
D019380:Anti-HIV Agents; D013386:Succinates; D014315:Triterpenes; C479935:bevirimat; D053978:Pentacyclic Triterpenes