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Research ArticleArticle

The Pharmacokinetics of a Thiazole Benzenesulfonamide β3-Adrenergic Receptor Agonist and Its Analogs in Rats, Dogs, and Monkeys: Improving Oral Bioavailability

Ralph A. Stearns, Randy R. Miller, Wei Tang, Gloria Y. Kwei, Frank S. Tang, Robert J. Mathvink, Elizabeth M. Naylor, Dawn Chitty, Vincent J. Colandrea, Ann E. Weber, Adria E. Colletti, John R. Strauss, Carol Ann Keohane, William P. Feeney, Susan A. Iliff and Shuet-Hing Lee Chiu
Drug Metabolism and Disposition July 2002, 30 (7) 771-777; DOI: https://doi.org/10.1124/dmd.30.7.771
Ralph A. Stearns
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Randy R. Miller
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Wei Tang
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Gloria Y. Kwei
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Frank S. Tang
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Robert J. Mathvink
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Elizabeth M. Naylor
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Dawn Chitty
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Vincent J. Colandrea
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Ann E. Weber
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Adria E. Colletti
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John R. Strauss
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Carol Ann Keohane
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William P. Feeney
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Susan A. Iliff
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Shuet-Hing Lee Chiu
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Abstract

The pharmacokinetics and oral bioavailability of (R)-N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-[4-(trifluoromethylphenyl]thiazol-2-yl]benzenesulfonamide ( 1 ), a 3-pyridyl thiazole benzenesulfonamide β3-adrenergic receptor agonist, were investigated in rats, dogs, and monkeys. Systemic clearance was higher in rats (∼30 ml/min/kg) than in dogs and monkeys (both ∼10 ml/min/kg), and oral bioavailability was 17, 27, and 4%, respectively. Since systemic clearance was 25 to 40% of hepatic blood flow in these species, hepatic extraction was expected to be low, and it was likely that oral bioavailability was limited either by absorption or a large first-pass effect in the gut. The absorption and excretion of3H-labeled 1 were investigated in rats, and only 28% of the administered radioactivity was orally absorbed. Subsequently, the hepatic extraction of 1 was evaluated in rats (30%) and monkeys (47%). The low oral bioavailability in rats could be explained completely by poor oral absorption and hepatic first-pass metabolism; in monkeys, oral absorption was either less than in rats or first-pass extraction in the gut was greater. In an attempt to increase oral exposure, the pharmacokinetics and oral bioavailability of two potential prodrugs of 1 , an N-ethyl [(R)-N-[4-[2-[ethyl[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-[4-(trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide; 2 ] and a morpholine derivative [(R)-N-[4-[2-[2-(3-pyridinyl)morpholin-4-yl]ethyl]phenyl]-4-[4-[4-(trifluoromethyl)- phenyl]thiazol-2-yl]benzenesulfonamide; 3 ], were evaluated in monkeys. Conversion to 1 was low (<3%) with both derivatives, and neither entity was an effective prodrug, but the oral bioavailability of 3 (56%) compared with 1 (4%) was significantly improved. The hypothesis that the increased oral bioavailability of 3 was due to a reduction in hydrogen bonding sites in the molecule led to the design of (R)-N-[4-[2-[[2-hydroxy-2-(pyridin-2-yl)ethyl]amino]ethyl]phenyl]-4-[4-(4-trifluoromethylphenyl)thiazol-2-yl]benzenesulfonamide ( 4 ), a 2-pyridyl β3-adrenergic receptor agonist with improved oral bioavailability in rats and monkeys.

Footnotes

  • ↵2 Subsequently, the disposition of 1and 4 were evaluated in brain and plasma after i.v. dosing in CF1 mdr1a +/+ and −/− mice (data not shown). Plasma concentrations of both drugs were similar in each strain of mice, but the concentrations in brain were 5- to 7-fold higher in the −/− strain. This data suggested that both 1 and 4 were P-glycoprotein substrates and that the increased oral absorption of4 was not due to a difference in P-glycoprotein substrate selectivity but rather to an improvement in the intrinsic membrane permeability of this analogue.

  • Abbreviations used are::
    1
    (R)-N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-[4-(trifluoromethylphenyl]thiazol-2-yl]benzenesulfonamide
    2
    (R)-N-[4-[2-[ethyl[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-4-(trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide
    3
    (R)-N-[4-[2-[2-(3-pyridinyl)morpholin-4-yl]ethyl]phenyl]-4-[4-[4-(trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide
    4
    (R)-N-[4-[2-[[2-hydroxy-2-(pyridin-2-yl)ethyl]amino]ethyl]phenyl]-4-[4-(4-trifluoromethylphenyl)thiazol-2-yl]benzenesulfonamide
    5, (R)-4-[5-(3,4-difluorophenylmethyl)-1,2,4-oxadiazol-3-yl]-N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino] ethyl]phenyl]benzenesulfonamide
    HPLC, high pressure liquid chromatography
    TFA
    trifluoroacetic acid
    PEG 400
    polyethylene glycol 400
    LC-MS/MS
    liquid chromatography-tandem mass spectrometry
    AUC
    area under the plasma concentration-time curve
    Clp
    plasma clearance
    Vdss
    volume of distribution at steady state
    • Received November 2, 2001.
    • Accepted March 18, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (7)
Drug Metabolism and Disposition
Vol. 30, Issue 7
1 Jul 2002
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Research ArticleArticle

The Pharmacokinetics of a Thiazole Benzenesulfonamide β3-Adrenergic Receptor Agonist and Its Analogs in Rats, Dogs, and Monkeys: Improving Oral Bioavailability

Ralph A. Stearns, Randy R. Miller, Wei Tang, Gloria Y. Kwei, Frank S. Tang, Robert J. Mathvink, Elizabeth M. Naylor, Dawn Chitty, Vincent J. Colandrea, Ann E. Weber, Adria E. Colletti, John R. Strauss, Carol Ann Keohane, William P. Feeney, Susan A. Iliff and Shuet-Hing Lee Chiu
Drug Metabolism and Disposition July 1, 2002, 30 (7) 771-777; DOI: https://doi.org/10.1124/dmd.30.7.771

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Research ArticleArticle

The Pharmacokinetics of a Thiazole Benzenesulfonamide β3-Adrenergic Receptor Agonist and Its Analogs in Rats, Dogs, and Monkeys: Improving Oral Bioavailability

Ralph A. Stearns, Randy R. Miller, Wei Tang, Gloria Y. Kwei, Frank S. Tang, Robert J. Mathvink, Elizabeth M. Naylor, Dawn Chitty, Vincent J. Colandrea, Ann E. Weber, Adria E. Colletti, John R. Strauss, Carol Ann Keohane, William P. Feeney, Susan A. Iliff and Shuet-Hing Lee Chiu
Drug Metabolism and Disposition July 1, 2002, 30 (7) 771-777; DOI: https://doi.org/10.1124/dmd.30.7.771
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