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Research ArticleArticle

Biotransformation of Tirilazad in Human: 3. Tirilazad A-Ring Reduction by Human Liver Microsomal 5α-Reductase Type 1 and Type 2

Larry C. Wienkers, Rick C. Steenwyk, Michael J. Hauer, Joseph C. Fleishaker and Paul G. Pearson
Journal of Pharmacology and Experimental Therapeutics November 1998, 287 (2) 583-590;
Larry C. Wienkers
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Rick C. Steenwyk
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Michael J. Hauer
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Joseph C. Fleishaker
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Paul G. Pearson
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Abstract

Tirilazad mesylate (FREEDOX), a potent inhibitor of membrane lipid peroxidation in vitro, is under clinical development for the treatment of subarachnoid hemorrhage. In humans, tirilazad is cleared almost exclusively via hepatic elimination with a medium-to-high extraction ratio. In human liver microsomal preparations, tirilazad is biotransformed to multiple oxidative products and one reduced, pharmacologically active metabolite, U-89678. Characterization of the reduced metabolite by mass spectrometry and cochromatography with an authentic standard demonstrated that U-89678 was formed via stereoselective reduction of the Δ4 bond in the steroid A-ring. Kinetic analysis of tirilazad reduction in human liver microsomes revealed that kinetically distinct type 1 and type 2 5α-reductase enzymes were responsible for U-89678 formation; the apparent KM values for type 2 and type 1 were ∼15 and ∼0.5 μM, respectively. Based on pH dependence and finasteride inhibition studies, it was inferred that 5α-reductase type 1 was the high affinity/low capacity microsomal reductase that contributed to tirilazad clearance in vivo. In addition, a role for CYP3A4 in the metabolism of U-89678 was established using cDNA expressed CYP3A4 and correlation studies comparing U-89678 consumption with cytochrome P450 activities across a population of human liver microsomes. Collectively, these data suggest that formation of U-89678, a circulating pharmacologically active metabolite, contributes to the total metabolic elimination of tirilazad in humans and that clearance of U-89678 is mediated primarilyvia CYP3A4 metabolism. Therefore, concurrent administration of therapeutic agents that modulate 5α-reductase type 1 or CYP3A activity are anticipated to affect the pharmacokinetics of PNU-89678.

Footnotes

  • Send reprint requests to: Dr. Paul G. Pearson, Department of Drug Metabolism, Merck Research Laboratories, Merck & Co. Inc., P.O. Box 4, WP 26A-2044, West Point, PA 19486-0004. E-mail:Paul_Pearson{at}Merck.com

  • Abbreviations:
    P450 or CYP
    cytochrome P450
    HPLC
    high performance liquid chromatography
    CI
    chemical ionization
    EI
    electron ionization
    PB/LC-MS
    particle beam/liquid chromatography mass spectrometry
    ESI/MS
    electrospray ionization mass spectrometry
    APCI
    atmospheric pressure chemical ionization
    • Received January 21, 1998.
    • Accepted June 2, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 2
1 Nov 1998
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Research ArticleArticle

Biotransformation of Tirilazad in Human: 3. Tirilazad A-Ring Reduction by Human Liver Microsomal 5α-Reductase Type 1 and Type 2

Larry C. Wienkers, Rick C. Steenwyk, Michael J. Hauer, Joseph C. Fleishaker and Paul G. Pearson
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 583-590;

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Research ArticleArticle

Biotransformation of Tirilazad in Human: 3. Tirilazad A-Ring Reduction by Human Liver Microsomal 5α-Reductase Type 1 and Type 2

Larry C. Wienkers, Rick C. Steenwyk, Michael J. Hauer, Joseph C. Fleishaker and Paul G. Pearson
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 583-590;
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