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Research ArticleArticle

Pharmacokinetics and Metabolism of the Prodrug DB289 (2,5-Bis[4-(N-methoxyamidino)phenyl]furan Monomaleate) in Rat and Monkey and Its Conversion to the Antiprotozoal/Antifungal Drug DB75 (2,5-Bis(4-guanylphenyl)furan Dihydrochloride)

Ian Midgley, Karen Fitzpatrick, Lynne M. Taylor, Tara L. Houchen, Simon J. Henderson, Sarah J. Wright, Zbigniew R. Cybulski, Brian A. John, Alan McBurney, David W. Boykin and Kerri L. Trendler
Drug Metabolism and Disposition June 2007, 35 (6) 955-967; DOI: https://doi.org/10.1124/dmd.106.013391
Ian Midgley
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Karen Fitzpatrick
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Lynne M. Taylor
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Tara L. Houchen
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Simon J. Henderson
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Sarah J. Wright
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Zbigniew R. Cybulski
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Brian A. John
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Alan McBurney
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David W. Boykin
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Kerri L. Trendler
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Abstract

DB289 (pafuramidine maleate; 2,5-bis[4-(N-methoxyamidino)phenyl]furan monomaleate) is a prodrug of DB75 (furamidine dihydrochloride; 2,5-bis(4-guanylphenyl)furan dihydrochloride), an aromatic dication related to pentamidine that has demonstrated good efficacy against African trypanosomiasis, Pneumocystis carinii pneumonia, and malaria, but lacks adequate oral availability. The pharmacokinetics and metabolism of 14C-DB289 have been investigated in rat and monkey after oral and intravenous administration. Oral doses were well absorbed (∼50-70%) and effectively converted to DB75 in both species but subject to first-pass metabolism and hepatic retention, limiting its systemic bioavailability to 10 to 20%. Clearance of DB289 approximated the liver plasma flow and its large volume of distribution was consistent with extensive tissue binding. Plasma protein binding of DB289 was 97 to 99% in four animal species and humans, but that of DB75 was noticeably less and more species- and concentration-dependent. Together, prodrug and active metabolite accounted for less than 20% of the plasma radioactivity after an oral dose, but DB75 was the major radiochemical component in key organs such as brain and liver and was largely responsible for the persistence of 14C in the body. The predominant route of excretion of radioactivity was via the feces, although biliary secretion was not particularly extensive. High-performance liquid chromatography and liquid chromatography-mass spectrometry investigations showed that the formation of DB75 from the prodrug involved the sequential loss of the two N-methoxy groups, either directly or by O-demethylation followed by reduction of the resulting oxime to the amidine. It was estimated that almost half of an oral dose of DB289 to rats and about one-third of that to monkeys was metabolized to DB75.

Footnotes

  • This work was supported by the Bill & Melinda Gates Foundation (Grant 3436: Development of Novel Drug Candidates for the Treatment of Human African Trypanosomiasis and Leishmaniasis).

  • This article is dedicated to the memory of Dr. James L. Allen of Immtech Pharmaceuticals, Inc., a highly respected colleague who was closely involved in the development of DB289, but who tragically passed away during preparation of the manuscript.

  • doi:10.1124/dmd.106.013391.

  • ABBREVIATIONS: PCP, Pneumocystis carinii pneumonia; CSF, cerebrospinal fluid; DB75, 2,5-bis(4-guanylphenyl)furan dihydrochloride; DB289, 2,5-bis[4-(N-methoxyamidino)phenyl]furan monomaleate; HPLC, high-performance liquid chromatography; LC-MS, liquid chromatography-mass spectrometry; LC-MS/MS, liquid chromatography-tandem mass spectrometry; QWBA, quantitative whole-body autoradiography; AUC, area under the curve; CL, clearance; AUMC, area under the first moment curve; ESI, electrospray ionization.

  • ↵1 Current affiliation: NPS Pharmaceuticals, Salt Lake City, Utah.

    • Received November 1, 2006.
    • Accepted March 12, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 35 (6)
Drug Metabolism and Disposition
Vol. 35, Issue 6
1 Jun 2007
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Pharmacokinetics and Metabolism of the Prodrug DB289 (2,5-Bis[4-(N-methoxyamidino)phenyl]furan Monomaleate) in Rat and Monkey and Its Conversion to the Antiprotozoal/Antifungal Drug DB75 (2,5-Bis(4-guanylphenyl)furan Dihydrochloride)
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Research ArticleArticle

Pharmacokinetics and Metabolism of the Prodrug DB289 (2,5-Bis[4-(N-methoxyamidino)phenyl]furan Monomaleate) in Rat and Monkey and Its Conversion to the Antiprotozoal/Antifungal Drug DB75 (2,5-Bis(4-guanylphenyl)furan Dihydrochloride)

Ian Midgley, Karen Fitzpatrick, Lynne M. Taylor, Tara L. Houchen, Simon J. Henderson, Sarah J. Wright, Zbigniew R. Cybulski, Brian A. John, Alan McBurney, David W. Boykin and Kerri L. Trendler
Drug Metabolism and Disposition June 1, 2007, 35 (6) 955-967; DOI: https://doi.org/10.1124/dmd.106.013391

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Research ArticleArticle

Pharmacokinetics and Metabolism of the Prodrug DB289 (2,5-Bis[4-(N-methoxyamidino)phenyl]furan Monomaleate) in Rat and Monkey and Its Conversion to the Antiprotozoal/Antifungal Drug DB75 (2,5-Bis(4-guanylphenyl)furan Dihydrochloride)

Ian Midgley, Karen Fitzpatrick, Lynne M. Taylor, Tara L. Houchen, Simon J. Henderson, Sarah J. Wright, Zbigniew R. Cybulski, Brian A. John, Alan McBurney, David W. Boykin and Kerri L. Trendler
Drug Metabolism and Disposition June 1, 2007, 35 (6) 955-967; DOI: https://doi.org/10.1124/dmd.106.013391
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