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Research ArticleArticle

Substance P Receptor Antagonist I: Conversion of Phosphoramidate Prodrug after i.v. Administration to Rats and Dogs

Su-Er W. Huskey, Debra Luffer-Atlas, Brian J. Dean, Erin M. McGowan, William P. Feeney and Shuet-Hing Lee Chiu
Drug Metabolism and Disposition November 1999, 27 (11) 1367-1373;
Su-Er W. Huskey
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Debra Luffer-Atlas
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Brian J. Dean
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Erin M. McGowan
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William P. Feeney
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Shuet-Hing Lee Chiu
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Abstract

A water-soluble phosphoramidate prodrug (L-758,298, compound I) of the potent and selective human Substance P receptor antagonist L-754,030 (compound II) is under development as an i.v. drug for treatment of emesis, migraine, and chronic pain. Compound I undergoes hydrolysis readily to II under acidic conditions. In the studies reported herein, we investigated the stability of I in blood and hepatic subcellular fractions from rats, dogs, and humans as well as the conversion of I to II in rats and dogs after i.v. dosing. Compound I was converted to II rapidly in rat blood but was stable in dog and human blood. However, the conversion was rapid in liver microsomes prepared from dogs and humans. As expected from the results of in vitro studies, the in vivo conversion of I to II was rapid after i.v. dosing of I to rats and dogs. The relative extent of exposure of II after i.v. dosing of I was estimated by comparing the dose-adjusted area under the plasma concentration versus time curve values of II after i.v. dosing of I with those after i.v. dosing of II. In rats, the extent of exposure was estimated to be ∼90 and ∼100% at 1 and 8 mg/kg, respectively; in dogs, that was ∼59% at 0.5 mg/kg. A nonproportional increase in the area under the concentration versus time curve value of II with dose was observed after i.v. administration of I in dogs from 0.5 to 32 mg/kg, suggesting that the elimination of II might have been saturated at higher doses.

Footnotes

  • Send reprint requests to: Dr. Su-Er W. Huskey, Dept. of Drug Metabolism, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065. E-mail: su_huskey{at}merck.com

  • Abbreviations used are::
    L-754,030 (II)
    [(2R)-((1R)-3,5-bis(trifluoromethylphenyl)ethoxy)-(3S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine]
    L-758,298 (I)
    [(2R)-(1-(R)-3,5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1-phosphoryl-5-oxo-4H-1,2,4-triazolo)methylmorpholine
    Compound III
    [(2R)-(3,5-bis(trifluoromethyl)benzyloxy)-(3S)-phenyl-4-(3-(1-phosphoryl-5-oxo-4H-1,2,4-triazolo)methylmorpholine
    Compound IV
    [(2R)-((1R)-3,5-bis(trifluoromethylphenyl)ethoxy)-(3S)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine]
    AUC
    area under the plasma concentration versus time curve
    PEG400
    polyethylene glycol
    SD
    Sprague-Dawley
    LC-MS/MS
    liquid chromatography-tandem mass spectrometry
    SRM
    selected reaction monitoring
    Vdss
    volume of distribution at steady state
    • Received February 26, 1999.
    • Accepted August 10, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (11)
Drug Metabolism and Disposition
Vol. 27, Issue 11
1 Nov 1999
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Research ArticleArticle

Substance P Receptor Antagonist I: Conversion of Phosphoramidate Prodrug after i.v. Administration to Rats and Dogs

Su-Er W. Huskey, Debra Luffer-Atlas, Brian J. Dean, Erin M. McGowan, William P. Feeney and Shuet-Hing Lee Chiu
Drug Metabolism and Disposition November 1, 1999, 27 (11) 1367-1373;

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Research ArticleArticle

Substance P Receptor Antagonist I: Conversion of Phosphoramidate Prodrug after i.v. Administration to Rats and Dogs

Su-Er W. Huskey, Debra Luffer-Atlas, Brian J. Dean, Erin M. McGowan, William P. Feeney and Shuet-Hing Lee Chiu
Drug Metabolism and Disposition November 1, 1999, 27 (11) 1367-1373;
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