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Structural Characterization of Anti-HIV Drug Candidate PA-457 [3-O-(3′,3′-Dimethylsuccinyl)-betulinic acid] and Its Acyl Glucuronides in Rat Bile and Evaluation of in Vitro Stability in Human and Animal Liver Microsomes and Plasma

Zhiming Wen, Stephan T. Stern, David E. Martin, Kuo-Hsiung Lee and Philip C. Smith
Drug Metabolism and Disposition September 2006, 34 (9) 1436-1442; DOI: https://doi.org/10.1124/dmd.106.009233
Zhiming Wen
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Stephan T. Stern
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David E. Martin
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Kuo-Hsiung Lee
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Philip C. Smith
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Abstract

PA-457 [3-O-(3′,3′-dimethylsuccinyl)-betulinic acid] represents a new class of anti-HIV drug candidates termed maturation inhibitors. After oral administration to rats, PA-457 was metabolized to several glucuronide conjugates and mainly eliminated into rat bile. Liquid chromatography-electrospray ionization-mass spectrometry analysis showed that the glucuronidation products of PA-457 were acyl glucuronides including one di-glucuronide, di-PA-457G, and two mono-glucuronides, referred to as mono-PA-457G (I) and mono-PA-457G (II), respectively. In-source fragmentation of MS spectra supported the conclusion that mono-PA-457G (I) was glucuronidated at the C-28 carboxyl of PA-457, whereas mono-PA-457G (II) was conjugated at the dimethylsuccinic acid side chain of the C-3 position. Quantification demonstrated that the predominant glucuronide of PA-457 in rat bile was mono-PA-457G (I) with lower amounts of mono-PA-457G (II) and di-PA-457G. In vitro stability indicated that the mono-acyl glucuronides of PA-457 were not degraded after incubation with 0.1 M phosphate buffer (pH 4, 7.4 and 9), plasma (human, rat, and mouse), and UDP-glucuronosyltransferase reaction media (without uridine 5′-diphosphoglucuronic acid) with microsomes (human, rat, and mouse liver microsomes), respectively, whereas the minor diglucuronide was unstable in rodent liver microsomes. All glucuronides of PA-457 could be hydrolyzed both by β-glucuronidase and alkaline (1 M NaOH). Minor putative acyl migration products were slowly formed at pH 9, suggesting that the acyl glucuronides of PA-457 have relatively high in vitro stability.

Footnotes

  • This investigation was supported by Panacos Pharmaceuticals and, in part, by Grant AI-33066 from the National Institute of Allergy and Infectious Diseases awarded to K.H.L.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.106.009233.

  • ABBREVIATIONS: PA-457, 3-O-(3′,3′-dimethylsuccinyl)-betulinic acid; DSD, 3-O-(3′,3′-dimethylsuccinyl)-dihydrobetulinic acid; PA-457G, acyl glucuronide of PA-457; UDPGA, uridine 5′-diphosphoglucuronic acid; HPLC, high-performance liquid chromatography; LC-ESI-MS, liquid chromatography-electrospray ionization-mass spectrometry; d-SL, d-saccharic acid 1,4-lactone; PMSF, phenylmethylsulfonyl fluoride; HLM, human liver microsome; RLM, rat liver microsome; ACN, acetonitrile; SPE, solid-phase extraction; HAc, glacial acetic acid; IS, internal standard; MLM, mouse liver microsome; TIC, total ion chromatogram; tR, retention time.

  • ↵1 Current affiliation (S.T.S.): Nanotechnology Characterization Lab, SAIC-Frederick/NCI-Frederick, Frederick, MD 21702.

    • Received January 3, 2006.
    • Accepted May 31, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (9)
Drug Metabolism and Disposition
Vol. 34, Issue 9
1 Sep 2006
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OtherShort Communication

Structural Characterization of Anti-HIV Drug Candidate PA-457 [3-O-(3′,3′-Dimethylsuccinyl)-betulinic acid] and Its Acyl Glucuronides in Rat Bile and Evaluation of in Vitro Stability in Human and Animal Liver Microsomes and Plasma

Zhiming Wen, Stephan T. Stern, David E. Martin, Kuo-Hsiung Lee and Philip C. Smith
Drug Metabolism and Disposition September 1, 2006, 34 (9) 1436-1442; DOI: https://doi.org/10.1124/dmd.106.009233

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OtherShort Communication

Structural Characterization of Anti-HIV Drug Candidate PA-457 [3-O-(3′,3′-Dimethylsuccinyl)-betulinic acid] and Its Acyl Glucuronides in Rat Bile and Evaluation of in Vitro Stability in Human and Animal Liver Microsomes and Plasma

Zhiming Wen, Stephan T. Stern, David E. Martin, Kuo-Hsiung Lee and Philip C. Smith
Drug Metabolism and Disposition September 1, 2006, 34 (9) 1436-1442; DOI: https://doi.org/10.1124/dmd.106.009233
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