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Drug Metabolism & Disposition

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Research ArticleArticle

Disposition and Chemical Stability of Telmisartan 1-O-Acylglucuronide

T. Ebner, G. Heinzel, A. Prox, K. Beschke and H. Wachsmuth
Drug Metabolism and Disposition October 1999, 27 (10) 1143-1149;
T. Ebner
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G. Heinzel
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A. Prox
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K. Beschke
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H. Wachsmuth
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Abstract

Telmisartan 1-O-acylglucuronide, the principal metabolite of telmisartan in humans, was characterized in terms of chemical stability and the structure of its isomerization products was elucidated. In addition, pharmacokinetics of telmisartan 1-O-acylglucuronide were assessed in rats after i.v. dosing. Similar to other acylglucuronides, telmisartan 1-O-acylglucuronide and diclofenac 1-O-acylglucuronide, which was used for comparison, showed the formation of different isomeric acylglucuronides on incubation in aqueous buffer. The isomeric acylglucuronides of telmisartan consisted of the 2-O-, 3-O-, and 4-O-acylglucuronides (α,β-anomers). First order degradation half-lives of 26 and 0.5 h were observed on incubation in buffer of pH 7.4 for the 1-O-acylglucuronides of telmisartan and diclofenac, respectively. This indicated that the 1-O-acylglucuronide of telmisartan was among the most stable acylglucuronides reported to date. The high stability of telmisartan 1-O-acylglucuronide was confirmed by in vitro experiments that indicated only very low covalent binding of telmisartan acylglucuronide to human serum albumin but a considerable amount of covalently bound radioactivity with the acylglucuronide of diclofenac. After i.v. dosing to rats, telmisartan 1-O-acylglucuronide was rapidly cleared from plasma with a clearance of 180 ml/min/kg, compared with 15.6 ml/min/kg for the parent compound. Because telmisartan 1-O-acylglucuronide exhibited a comparably high chemical stability together with a high clearance that resulted in low systemic exposure, the amount of covalent binding to proteins should be negligible compared with other frequently used drugs, such as furosemide, ibuprofen, or salicylic acid.

Footnotes

  • Send reprint requests to: Dr. Thomas Ebner, Boehringer Ingelheim Pharma KG, Department of Pharmacokinetics and Drug Metabolism, Birkendorfer Str. 65, D-88397 Biberach, Germany.

  • This work has in part been presented on the 2ndInternational Symposium on Angiotensin II Antagonism, London, 15–18 February 1999.

  • Abbreviations used are::
    NSAID
    nonsteroidal anti-inflammatory drug
    HSA
    human serum albumin
    LSC
    liquid scintillation counting
    LC-MS
    liquid chromatography-mass spectrometry
    • Received March 22, 1999.
    • Accepted June 14, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (10)
Drug Metabolism and Disposition
Vol. 27, Issue 10
1 Oct 1999
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Research ArticleArticle

Disposition and Chemical Stability of Telmisartan 1-O-Acylglucuronide

T. Ebner, G. Heinzel, A. Prox, K. Beschke and H. Wachsmuth
Drug Metabolism and Disposition October 1, 1999, 27 (10) 1143-1149;

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Research ArticleArticle

Disposition and Chemical Stability of Telmisartan 1-O-Acylglucuronide

T. Ebner, G. Heinzel, A. Prox, K. Beschke and H. Wachsmuth
Drug Metabolism and Disposition October 1, 1999, 27 (10) 1143-1149;
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