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Research ArticleArticle

Conjugation of the Enantiomers of Ketotifen to Four Isomeric Quaternary Ammonium Glucuronides in Humans In Vivo and in Liver Microsomes

Udo Mey, Helmut Wachsmuth and Ursula Breyer-Pfaff
Drug Metabolism and Disposition November 1999, 27 (11) 1281-1292;
Udo Mey
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Helmut Wachsmuth
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Ursula Breyer-Pfaff
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Abstract

The antiallergic drug ketotifen is chiral due to a nonplanar seven-membered ring containing a keto group. Earlier studies have revealed glucuronidation at the tertiary amino group as a major metabolic pathway in humans. Chemical synthesis of glucuronides from racemic ketotifen now led to four isomers separable by HPLC of which two each could be ascribed to (R)-(+)- and(S)-(−)-ketotifen by synthesis from the enantiomers. According to 1H NMR analysis of the(S)-ketotifen N-glucuronides, the conformation of the piperidylidene ring differs between the two isomers. Enzymatic hydrolysis with Escherichia coliβ-glucuronidase proceeded at a lower rate with the slower eluting(S)-ketotifen glucuronide than with the three other isomers. On incubation of the ketotifen enantiomers (0.5–200 μM) with human liver microsomes in the presence of UDP-glucuronic acid and Triton X-100, the N-glucuronides of(R)-ketotifen were produced with an apparentKM 15 μM andVmax 470 pmol/min/mg protein. The two(S)-ketotifen glucuronides were formed by two-enzyme kinetics with KM1 1.3 μM andKM2 92 μM andVmax values of 60 and 440 pmol/min/mg protein. After ingestion of 1 mg of racemic ketotifen, 10 healthy subjects excreted in urine 17 ± 5% of the dose in the form ofN-glucuronides. The (R)-ketotifen glucuronide isomers contributed one-sixth only, whereas the remainder consisted primarily of the (S)-ketotifen glucuronide isomer, which eluted last. Differential hydrolysis or membrane transport may be responsible for the discrepancy betweenN-glucuronide isomer ratios in vitro and in vivo.

Footnotes

  • Send reprint requests to: Dr. Ursula Breyer-Pfaff, Department of Toxicology, University of Tuebingen, Wilhelmstrasse 56, D-72074 Tuebingen, Germany. E-mail:ursula.breyer-pfaff{at}uni-tuebingen.de

  • Abbreviations used are::
    UGT
    UDP-glucuronosyl transferase
    (R)- or (S)-GlucA or B
    glucuronides of (R)- or (S)-ketotifen
    ESI
    electrospray ionization
    CID
    collision-induced dissociation
    ax
    axial
    eq
    equatorial, HH COSY, Hartman-Hahn correlation spectroscopy
    HH ROESY
    Hartman-Hahn rotating-frame Overhauser effect spectroscopy
    • Received May 4, 1999.
    • Accepted July 15, 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

Conjugation of the Enantiomers of Ketotifen to Four Isomeric Quaternary Ammonium Glucuronides in Humans In Vivo and in Liver Microsomes

Udo Mey, Helmut Wachsmuth and Ursula Breyer-Pfaff
Drug Metabolism and Disposition November 1, 1999, 27 (11) 1281-1292;

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Research ArticleArticle

Conjugation of the Enantiomers of Ketotifen to Four Isomeric Quaternary Ammonium Glucuronides in Humans In Vivo and in Liver Microsomes

Udo Mey, Helmut Wachsmuth and Ursula Breyer-Pfaff
Drug Metabolism and Disposition November 1, 1999, 27 (11) 1281-1292;
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