A Dose-Ranging Study of Azathioprine Pharmacokinetics After Single-Dose Administration of a Delayed-Release Oral Formulation

Authors

  • Dr. Bradley J. Zins MD,

    1. Inflammatory Bowel Disease Clinic in the Division of Gastroenterology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota.
    2. Division of Clinical Pharmacology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota.
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  • Dr. William J. Sandborn MD,

    Corresponding author
    1. Inflammatory Bowel Disease Clinic in the Division of Gastroenterology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota.
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  • Mr. Jeffrey A. McKinney BS,

    1. Division of Clinical Pharmacology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota.
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  • Dr. Dennis C. Mays PhD,

    1. Division of Clinical Pharmacology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota.
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  • Dr. Erik C. VAN Os MD,

    1. Inflammatory Bowel Disease Clinic in the Division of Gastroenterology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota.
    2. Division of Clinical Pharmacology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota.
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  • Dr. William J. Tremaine MD,

    1. Inflammatory Bowel Disease Clinic in the Division of Gastroenterology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota.
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  • Dr. Douglas W. Mahoney MS,

    1. Section of Biostatistics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota.
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  • Dr. Alan R. Zinsmeister PhD,

    1. Section of Biostatistics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota.
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  • Dr. James J. Lipsky MD

    1. Division of Clinical Pharmacology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota.
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Mayo Clinic, 200 First Street SW, Rochester, MN 55905.

Abstract

6-Mercaptopurine and its prodrug azathioprine are an effective treatment for inflammatory bowel disease, but widespread use has been limited by concern about toxicity. Ileocolonic delivery of azathioprine as a 50-mg delayed-release oral capsule has been shown to decrease bioavailability, thus potentially decreasing toxicity. This study aimed to determine the bioavailability and pharmacokinetic parameters of delayed-release oral azathioprine capsules at doses of 200 mg, 400 mg, and 600 mg relative to 100 mg of standard oral azathioprine tablets. Thirty healthy human volunteers each received delayed-release oral azathioprine at one of the three doses (n = 10 for each group). All participants also received a 100-mg tablet of standard oral azathioprine. Plasma concentrations of 6-mercaptopurine were determined by high-pressure liquid chromatography. The relative bioavailabilities of 6-mercaptopurine after ileocolonic azathioprine administration via delayed-release oral capsules at doses of 200 mg, 400 mg, and 600 mg (means of 15%, 15%, and 12%, respectively) were all significantly less than 100% compared with standard oral azathioprine at a 100-mg dose. Ileocolonic delivery of azathioprine by a delayed-release oral capsule formulation at doses up to 600 mg considerably reduces 6-mercaptopurine bioavailability, relative to standard oral azathioprine tablets. The therapeutic potential of this ileocolonic delivery formulation, which can limit toxicity by local delivery of azathioprine, should be investigated in patients with inflammatory bowel disease.

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