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

School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (Z.W., K.-H.L., P.C.S.); and Research and Development Center, Panacos Pharmaceuticals, Gaithersburg, Maryland (D.E.M., P.B.)

Bevirimat [BVM, PA-457, 3-O-(3',3'-dimethylsuccinyl)-betulinic acid], a new anti-human immunodeficiency virus drug candidate, is metabolized to two monoglucuronides [mono-BVMG (I) and mono-BVMG (II)] and one diglucuronide (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 microsomes (HLMs) and human intestinal microsomes (HIMs), animal liver microsomes, and 12 recombinant human UGT isoforms. Glucuronidation of BVM with HLMs predominantly involved the formation of mono-BVMG (I) (V_max = 61 pmol/min/mg protein, K_m = 27 µM) and mono-BVMG (II) (V_max = 48 pmol/min/mg protein, K_m = 16 µM). Di-BVMG was also observed but was a minor metabolite. HIMs mainly revealed glucuronidation to form mono-BVMG (II) (V_max = 90 pmol/min/mg of protein, K_m = 8.3 µM). UGT1A3 predominantly formed mono-BVMG (I) (V_max = 65 pmol/min/mg of protein, K_m = 13 µM), whereas UGT1A4 is a less active isoform (V_max = 1.8 pmol/min/mg of protein, K_m = 5.6 µM). UGT2B7 was involved in the formation of both mono-BVMG (I) (V_max = 6.1 pmol/min/mg of protein, K_m = 6.0 µM) and mono-BVMG (II) (V_max = 6.5 pmol/min/mg of protein, K_m = 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 a higher formation rate for mono-BVMG (I), whereas marmoset liver microsomes showed a higher formation rate for mono-BVMG (II). The data suggest a primary role of UGT1A3 for the glucuronidation of BVM.

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