Modeling of Relationships between Pharmacokinetics and Blockade of Agonist-Induced Elevation of Intraurethral Pressure and Mean Arterial Pressure in Conscious Dogs Treated with α1-Adrenoceptor Antagonists

  1. David G. Witte,
  2. Michael E. Brune,
  3. Sweta P. Katwala,
  4. Ivan Milicic,
  5. Deanne Stolarik,
  6. Yu-Hua Hui,
  7. Kennan C. Marsh,
  8. James F. Kerwin, Jr.,
  9. Michael D. Meyer and
  10. Arthur A. Hancock
  1. Pharmaceutical Products Discovery, Neurological Urological Disease Research, Abbott Laboratories, Abbott Park, Illinois
  1. David Witte, D-47MN, AP9A/2, Abbott Laboratories, 100 Abbott Park Rd., Abbott Park, IL 60064-6123. E-mail: david.g.witte{at}abbott.com

Abstract

Fiduxosin is a new α1-adrenoceptor antagonist targeted for the treatment of symptomatic benign prostatic hyperplasia. The purpose of this study was to determine and compare the potencies of the α1-adrenoceptor antagonists terazosin, doxazosin, tamsulosin, and fiduxosin, based on relationships between plasma drug concentrations and blockade of phenylephrine (PE)-induced intraurethral (IUP) and mean arterial pressure (MAP) responses after single oral dosing in conscious male beagle dogs. Magnitude of blockade and plasma concentrations were evaluated at selected time points over 24 h. All drugs produced dose-dependent antagonism of PE-induced IUP and MAP responses. When IUP and MAP blockade effects were plotted against drug plasma concentrations, direct relationships were observed that were well described by the sigmoidal maximal effect model. IUP IC50 values for terazosin, doxazosin, tamsulosin, and fiduxosin were 48.6, 48.7, 0.42, and 261 ng/ml, respectively. MAP IC50 values were 12.2, 13.8, 1.07, and 1904 ng/ml, respectively. Uroselectivity index values, defined as MAP IC50/IUP IC50, were 0.25, 0.28, 2.6, and 7.3, respectively. These results extend previous observations with terazosin in this model, showing that doxazosin exhibits a uroselectivity index comparable to terazosin, consistent with the lack of α1-adrenoceptor subtype selectivity or uroselectivity of these drugs. Tamsulosin, an α1a-/α1d-subtype selective agent, had an index value approximately 10-fold greater than the nonselective drugs. Based on its pharmacokinetic profile and a relative uroselectivity 29-fold greater than the nonselective drugs, fiduxosin is expected to exhibit greater selectivity for urethral compared with vascular α1-adrenoceptors in human and should be a novel, long-acting, uroselective α1-adrenoceptor antagonist.

Footnotes

  • ↵2 Solutions of compound(s) were prepared based upon the free-base weight.

  • ↵3 Dose solutions of compound(s) were prepared based upon the salt weight.

  • ↵1 In this article, nomenclature used to differentiate among the subtypes of α1-adrenoceptors uses uppercase subscripted letters to describe tissue-sourced receptors and lowercase subscripts to define cloned receptors (Bylund et al., 1994).

  • Abbreviations:
    BPH
    benign prostatic hyperplasia
    fiduxosin (ABT-980)
    (3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexa-hydro-[1]benzopyrano[3,4-c]pyrrol-2-yl)butyl]-8-phenyl-pyrazino[2′,3′:4,5]thieno-[3,2-d]pyrimidine-2,4(1H,3H)-dione))
    REC 15/2739
    (N-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxamide)
    PE
    phenylephrine
    MAP
    mean arterial pressure
    IUP
    intra-urethral pressure
    PK
    pharmacokinetics
    PD
    pharmacodynamics
    TFA
    trifluoroacetic acid
    A-86192 (N-[2-benzofuran-6-yl)ethyl]-N-[(R)-5,6-methylenedioxy-1,2,3,4-tetra-hydronaphthalen-1-ylmethyl]-N-methylamine mathanesulfonate)
    A-131701 (3-[2-((3aR,9bR)-cis-6-methoxy-2,3,3a,4,5,9b,hexa-hydro-[1H]-benz[e]isoindol-2-yl)ethyl]pyrido[3′,4′:4,5]thieno[3,2-d]-pyrimidino-2,4(1H,3H)-dione)
    LC-MS
    liquid chromatography-mass spectrometry
    RSD
    relative standard deviation
    CL/F
    oral plasma clearance/oral bioavailability
    ANOVA
    analysis of variance
    AUC0-∞
    area under the plasma concentration-time curve
    AUCE
    area under the effect against time curve
    • Received July 24, 2001.
    • Accepted October 21, 2001.
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  1. doi: 10.1124/jpet.300.2.495 JPET February 1, 2002 vol. 300 no. 2 495-504
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