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Research ArticleArticle

Preclinical Pharmacokinetics and Interspecies Scaling of a Novel Vitronectin Receptor Antagonist

Keith W. Ward, Leonard M. Azzarano, William E. Bondinell, Russell D. Cousins, William F. Huffman, Dalia R. Jakas, Richard M. Keenan, Thomas W. Ku, Dave Lundberg, William H. Miller, Jayme A. Mumaw, Kenneth A. Newlander, Jill L. Pirhalla, Theresa J. Roethke, Kevin L. Salyers, Pamela R. Souder, Gary J. Stelman and Brian R. Smith
Drug Metabolism and Disposition November 1999, 27 (11) 1232-1241;
Keith W. Ward
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Leonard M. Azzarano
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William E. Bondinell
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Russell D. Cousins
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William F. Huffman
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Dalia R. Jakas
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Richard M. Keenan
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Thomas W. Ku
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Dave Lundberg
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William H. Miller
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Jayme A. Mumaw
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Kenneth A. Newlander
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Jill L. Pirhalla
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Theresa J. Roethke
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Kevin L. Salyers
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Pamela R. Souder
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Gary J. Stelman
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Abstract

Allometric scaling may be used in drug development to predict the pharmacokinetics of xenobiotics in humans from animal data. Although allometry may be successful for compounds that are excreted unchanged or that are oxidatively metabolized (with corrections for metabolic capacity), it has been more challenging for compounds excreted primarily as conjugates in bile. (S)-10,11-Dihydro-3-[3-(pyridin-2-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetic acid (SB-265123) is a novel αvβ3 (“vitronectin receptor”) antagonist. In this study, the in vivo pharmacokinetics and in vitro plasma protein binding of SB-265123 were examined in four species: mice, rats, dogs, and monkeys. In monkeys and dogs, SB-265123 exhibited moderate clearance, whereas low clearance (<20% hepatic blood flow) was observed in the rat, and high clearance (>70% hepatic blood flow) was seen in the mouse. The concentration-time profiles indicated the possibility of enterohepatic recirculation; subsequent studies in bile duct-cannulated rats demonstrated extensive biliary excretion of an acyl-glucuronide of SB-265123. In allometric scaling to predict the disposition of SB-265123 in humans, various standard correction factors were applied, including protein binding, maximum lifespan potential, and brain weight; each failed to produce adequate interspecies scaling of clearance (r2< 0.72). Consequently, a novel correction factor incorporating bile flow and microsomal UDP-glucuronosyltransferase activity in each species was applied, demonstrating substantial improvement in the correlation of the allometric plot (r2= 0.96). This study demonstrates a novel allometric correction that may be applicable to compounds that undergo conjugation and biliary excretion.

Footnotes

  • Send reprint requests to: Keith W. Ward, Ph.D., Drug Metabolism and Pharmacokinetics, SmithKline Beecham Pharmaceuticals R&D, UW 2720, 709 Swedeland Rd., King of Prussia, PA 19406. E-mail:Keith_W_Ward{at}sbphrd.com

  • ↵1 This work presented in part at the 1999 Annual Society of Toxicology Meeting, March 14–18, New Orleans, LA.

  • Abbreviations used are::
    MS
    mass spectrometry
    MS/MS
    dual mass spectrometry
    CL
    plasma clearance
    Vdss
    steady-state volume of distribution
    fb and fu
    unbound and bound fraction in plasma
    Qbile
    bile flow rate
    UDPGT
    UDP-glucuronosyl transferase
    • Received March 16, 1999.
    • Accepted July 2, 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

Preclinical Pharmacokinetics and Interspecies Scaling of a Novel Vitronectin Receptor Antagonist

Keith W. Ward, Leonard M. Azzarano, William E. Bondinell, Russell D. Cousins, William F. Huffman, Dalia R. Jakas, Richard M. Keenan, Thomas W. Ku, Dave Lundberg, William H. Miller, Jayme A. Mumaw, Kenneth A. Newlander, Jill L. Pirhalla, Theresa J. Roethke, Kevin L. Salyers, Pamela R. Souder, Gary J. Stelman and Brian R. Smith
Drug Metabolism and Disposition November 1, 1999, 27 (11) 1232-1241;

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Research ArticleArticle

Preclinical Pharmacokinetics and Interspecies Scaling of a Novel Vitronectin Receptor Antagonist

Keith W. Ward, Leonard M. Azzarano, William E. Bondinell, Russell D. Cousins, William F. Huffman, Dalia R. Jakas, Richard M. Keenan, Thomas W. Ku, Dave Lundberg, William H. Miller, Jayme A. Mumaw, Kenneth A. Newlander, Jill L. Pirhalla, Theresa J. Roethke, Kevin L. Salyers, Pamela R. Souder, Gary J. Stelman and Brian R. Smith
Drug Metabolism and Disposition November 1, 1999, 27 (11) 1232-1241;
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