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Drug Metabolism and Disposition Fast Forward
First published on December 6, 2006; DOI: 10.1124/dmd.106.012815

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Received for publication September 18, 2006.
Revised December 4, 2006.
Accepted for publication December 5, 2006.

Glucuronidation of Anti-HIV Drug Candidate Bevirimat: Identification of Human UDP-glucuronosyltransferases and Species Difference

Zhiming Wen 1, David Martin 2, Peter Bullock 2, K.H. Lee 1, Philip C. Smith 1*

1 U North Carolina at Chapel Hill 2 Panacos Pharmaceuticals

* Address correspondence to: E-mail: pcs{at}email.unc.edu

Abstract

Bevirimat [BVM, PA-457 or 3-O-(3',3'-dimethylsuccinyl)-betulinic acid], a new anti-HIV drug candidate, is metabolized to two mono-glucuronides [mono-BVMG (I) and mono-BVMG (II)] and one di-glucuronide (di-BVMG) both in vivo and in vitro. UDP-glucuronosyltransferase (UGT) reaction screening, enzyme kinetics and species differences for the glucuronidation of BVM in vitro were investigated with pooled human liver and intestinal microsomes (HLMs and HIMs), animal liver microsomes and 12 recombinant human UGT isoforms. Glucuronidation of BVM with HLMs predominantly involved in the formation of mono-BVMG (I) (Vmax = 61 pmol/min/mg protein, Km = 27 µM) and mono-BVMG (II) (Vmax = 48 pmol/min/mg protein, Km = 16 µM). Di-BVMG was also observed but was a minor metabolite. HIMs mainly revealed glucuronidation to form mono-BVMG (II) (Vmax = 90 pmol/min/mg protein, Km = 8.3 µM). UGT1A3 predominantly formed mono-BVMG (I) (Vmax = 65 pmol/min/mg protein, Km = 13 µM), whereas UGT1A4 is a less active isoform (Vmax = 1.8 pmol/min/mg protein, Km = 5.6 µM). UGT2B7 was involved in the formation of both mono-BVMG (I) (Vmax = 6.1 pmol/min/mg protein, Km = 6.0 µM) and mono-BVMG (II) (Vmax = 6.5 pmol/min/mg protein, Km = 7.8 µM). Among the animal liver microsomes examined, all species (rat, mouse, dog and marmoset) demonstrated conjugation to form both mono-BVMG (I) and mono-BVMG (II), with dog liver microsomes exhibiting higher formation rate for mono-BVMG (I), whereas marmoset liver microsomes showing higher formation rate for mono-BVMG (II). The data suggest a primary role of UGT1A3 for the glucuronidation of BVM.


Key words: drug development, glucuronidation, liver microsomes, UDP glucuronyltransferases


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