Glucuronidation of anti-HIV drug candidate bevirimat: identification of human UDP-glucuronosyltransferases and species differences.

Glucuronidation of anti-HIV drug candidate bevirimat: identification of human UDP-glucuronosyltransferases and species differences. Research Abstract Details 

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Glucuronidation of anti-HIV drug candidate bevirimat: identification of human UDP-glucuronosyltransferases and species differences. Abstract Text:

Zhiming Wen,David E Martin,Peter Bullock,Kuo-Hsiung Lee,Philip C Smith,

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 microM) and mono-BVMG (II) (V(max) = 48 pmol/min/mg protein, K(m) = 16 microM). 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 microM). UGT1A3 predominantly formed mono-BVMG (I) (V(max) = 65 pmol/min/mg of protein, K(m) = 13 microM), whereas UGT1A4 is a less active isoform (V(max) = 1.8 pmol/min/mg of protein, K(m) = 5.6 microM). UGT2B7 was involved in the formation of both mono-BVMG (I) (V(max) = 6.1 pmol/min/mg of protein, K(m) = 6.0 microM) and mono-BVMG (II) (V(max) = 6.5 pmol/min/mg of protein, K(m) = 7.8 microM). 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.

Glucuronidation of anti-HIV drug candidate bevirimat: identification of human UDP-glucuronosyltransferases and species differences. Publishing Authors By Initials

Z Wen,DE Martin,P Bullock,KH Lee,PC Smith,

For similar organic chemicals: hydrocarbons: terpenes: triterpenes research abstracts see: organic chemicals: hydrocarbons: terpenes: triterpenes research

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Glucuronidation of anti-HIV drug candidate bevirimat: identification of human UDP-glucuronosyltransferases and species differences. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Drug metabolism and disposition: the biological fa

VOLUME: 35

Page Numbers: 440-8

Journal Abbreviation: Drug Metab. Dispos.

ISSN: 0090-9556

DAY: 6

MONTH: 12

YEAR: 2006

Glucuronidation of anti-HIV drug candidate bevirimat: identification of human UDP-glucuronosyltransferases and species differences. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 9421550

Glucuronidation of anti-HIV drug candidate bevirimat: identification of human UDP-glucuronosyltransferases and species differences. Keywords Mesh Terms:

KEYWORDS: Triterpenes

MESH TERMS: metabolism

Chemical & Substance for Abstract: Glucuronidation of anti-HIV drug candidate bevirimat: identification of human UDP-glucuronosyltransferases and species differences. Information

Substance Name: Glucuronosyltransferase

Registry Number: EC 2.4.1.17

Grant and Affiliation Information for Glucuronidation of anti-HIV drug candidate bevirimat: identification of human UDP-glucuronosyltransferases and species differences.

AFFILIATION: School of Pharmacy, CB 7360, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA.

Country: United States

AGENCY: United States NIAID

GRANT: AI33066

ACRONYM: AI

MEDLINETA: Drug Metab Dispos

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