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The absorption, distribution, metabolism and elimination of bevirimat in rats
Author(s) -
Bullock Peter,
Larsen Douglas,
Press Randy,
Wehrman Tod,
Martin David E.
Publication year - 2008
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.625
Subject(s) - bioavailability , pharmacokinetics , pharmacology , chemistry , absorption (acoustics) , dosing , oral administration , distribution (mathematics) , metabolism , excretion , medicine , biochemistry , mathematical analysis , physics , mathematics , acoustics
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 14 C‐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 ⩽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. Copyright © 2008 John Wiley & Sons, Ltd.