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Research ArticleArticle

Different Hydrolases Involved in Bioactivation of Prodrug-Type Angiotensin Receptor Blockers: Carboxymethylenebutenolidase and Carboxylesterase 1

Tomoko Ishizuka, Yasushi Yoshigae, Nobuyuki Murayama and Takashi Izumi
Drug Metabolism and Disposition November 2013, 41 (11) 1888-1895; DOI: https://doi.org/10.1124/dmd.113.053595
Tomoko Ishizuka
Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan
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Yasushi Yoshigae
Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan
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Nobuyuki Murayama
Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan
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Takashi Izumi
Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan
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Abstract

Olmesartan medoxomil (OM) is a prodrug-type angiotensin II type 1 receptor blocker (ARB). We recently identified carboxymethylenebutenolidase homolog (CMBL) as the responsible enzyme for OM bioactivation in humans. In the present study, we compared the bioactivating properties of OM with those of other prodrug-type ARBs, candesartan cilexetil (CC) and azilsartan medoxomil (AM), by focusing on interspecies differences and tissue specificity. In in-vitro experiments with pooled tissue subcellular fractions of mice, rats, monkeys, dogs, and humans, substantial OM-hydrolase activities were observed in cytosols of the liver, intestine, and kidney in all the species tested except for dog intestine, which showed negligible activity, whereas lung cytosols showed relatively low activities compared with the other tissues. AM-hydrolase activities were well correlated with the OM-hydrolase activities. In contrast, liver microsomes exhibited the highest CC-hydrolase activity among various tissue subcellular fractions in all the species tested. As a result of Western blot analysis with the tissue subcellular fractions, the band intensities stained with anti-human CMBL and carboxylesterase 1 (CES1) antibodies well reflected OM- and AM-hydrolase activities and CC-hydrolase activity, respectively, in animals and humans. Recombinant human CMBL and CES1 showed significant AM- and CC-hydrolase activities, respectively, whereas CC hydrolysis was hardly catalyzed with recombinant carboxylesterase 2 (CES2). In conclusion, OM is bioactivated mainly via intestinal and additionally hepatic CMBL not only in humans but also in mice, rats, and monkeys, while CC is bioactivated via hepatic CES1 rather than intestinal enzymes, including CES2. AM is a substrate for CMBL.

Footnotes

    • Received July 1, 2013.
    • Accepted August 13, 2013.
  • dx.doi.org/10.1124/dmd.113.053595.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (11)
Drug Metabolism and Disposition
Vol. 41, Issue 11
1 Nov 2013
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Research ArticleArticle

Bioactivation of ARB Prodrugs by CMBL and CES1

Tomoko Ishizuka, Yasushi Yoshigae, Nobuyuki Murayama and Takashi Izumi
Drug Metabolism and Disposition November 1, 2013, 41 (11) 1888-1895; DOI: https://doi.org/10.1124/dmd.113.053595

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Research ArticleArticle

Bioactivation of ARB Prodrugs by CMBL and CES1

Tomoko Ishizuka, Yasushi Yoshigae, Nobuyuki Murayama and Takashi Izumi
Drug Metabolism and Disposition November 1, 2013, 41 (11) 1888-1895; DOI: https://doi.org/10.1124/dmd.113.053595
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