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Identification of Major Esterase Involved in Hydrolysis of Soft Anticholinergic (2R3'R-SGM) Designed From Glycopyrrolate in Human and Rat Tissues.

Abstract

The glycopyrrolate soft analog, SGM, designed to be easily hydrolyzed into the significantly less active zwitterionic metabolite, SGa, typifies soft drug that reduces systemic side effects (a problem often seen with traditional anticholinergics) following local administration. In this study, hydrolysis of 2R3'R-SGM, the highest pharmacologically active stereoisomer of SGM, was investigated in human and rat tissues. In both species, 2R3'R-SGM was metabolized to 2R3'R-SGa in plasma but was stable in liver and intestine. The half-life of 2R3'R-SGM was found to be 16.9 min and 9.8 min in human and rat plasma, respectively. The enzyme inhibition and stimulation experiments showed that plasma paraoxonase 1 (PON1) is responsible for the hydrolysis of 2R3'R-SGM in humans and rats. The PON1-mediated hydrolysis of 2R3'R-SGM was confirmed in the lipoprotein-rich fractions of human plasma. As PON1 is naturally attached to high-density lipoprotein, it might be absent in topical tissues where 2R3'R-SGM is applied, supporting its local stability and efficacy. The metabolic behavior of 2R3'R-SGM indicates that it is an ideal soft drug to be detoxified as soon as it moves into systemic circulation. Furthermore, the similarity of 2R3'R-SGM metabolism in humans and rats showed that the rat is a suitable animal for preclinical study.

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  • Authors+Show Affiliations

    ,

    Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.

    ,

    Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto, Japan.

    ,

    Bodor Laboratories, Miami, Florida 33137; College of Pharmacy, University of Florida, Gainesville, Florida 32611.

    Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan. Electronic address: iteruko@gpo.kumamoto-u.ac.jp.

    Source

    Journal of pharmaceutical sciences 108:8 2019 Aug pg 2791-2797

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    30954525

    Citation

    Samir, Ahmed, et al. "Identification of Major Esterase Involved in Hydrolysis of Soft Anticholinergic (2R3'R-SGM) Designed From Glycopyrrolate in Human and Rat Tissues." Journal of Pharmaceutical Sciences, vol. 108, no. 8, 2019, pp. 2791-2797.
    Samir A, Ohura K, Bodor N, et al. Identification of Major Esterase Involved in Hydrolysis of Soft Anticholinergic (2R3'R-SGM) Designed From Glycopyrrolate in Human and Rat Tissues. J Pharm Sci. 2019;108(8):2791-2797.
    Samir, A., Ohura, K., Bodor, N., & Imai, T. (2019). Identification of Major Esterase Involved in Hydrolysis of Soft Anticholinergic (2R3'R-SGM) Designed From Glycopyrrolate in Human and Rat Tissues. Journal of Pharmaceutical Sciences, 108(8), pp. 2791-2797. doi:10.1016/j.xphs.2019.03.030.
    Samir A, et al. Identification of Major Esterase Involved in Hydrolysis of Soft Anticholinergic (2R3'R-SGM) Designed From Glycopyrrolate in Human and Rat Tissues. J Pharm Sci. 2019;108(8):2791-2797. PubMed PMID: 30954525.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Identification of Major Esterase Involved in Hydrolysis of Soft Anticholinergic (2R3'R-SGM) Designed From Glycopyrrolate in Human and Rat Tissues. AU - Samir,Ahmed, AU - Ohura,Kayoko, AU - Bodor,Nicholas, AU - Imai,Teruko, Y1 - 2019/04/05/ PY - 2019/01/29/received PY - 2019/03/19/revised PY - 2019/03/28/accepted PY - 2019/4/8/pubmed PY - 2019/4/8/medline PY - 2019/4/8/entrez KW - drug design KW - enzyme(s) KW - hydrolysis KW - metabolism KW - phase I enzyme(s) KW - protein binding SP - 2791 EP - 2797 JF - Journal of pharmaceutical sciences JO - J Pharm Sci VL - 108 IS - 8 N2 - The glycopyrrolate soft analog, SGM, designed to be easily hydrolyzed into the significantly less active zwitterionic metabolite, SGa, typifies soft drug that reduces systemic side effects (a problem often seen with traditional anticholinergics) following local administration. In this study, hydrolysis of 2R3'R-SGM, the highest pharmacologically active stereoisomer of SGM, was investigated in human and rat tissues. In both species, 2R3'R-SGM was metabolized to 2R3'R-SGa in plasma but was stable in liver and intestine. The half-life of 2R3'R-SGM was found to be 16.9 min and 9.8 min in human and rat plasma, respectively. The enzyme inhibition and stimulation experiments showed that plasma paraoxonase 1 (PON1) is responsible for the hydrolysis of 2R3'R-SGM in humans and rats. The PON1-mediated hydrolysis of 2R3'R-SGM was confirmed in the lipoprotein-rich fractions of human plasma. As PON1 is naturally attached to high-density lipoprotein, it might be absent in topical tissues where 2R3'R-SGM is applied, supporting its local stability and efficacy. The metabolic behavior of 2R3'R-SGM indicates that it is an ideal soft drug to be detoxified as soon as it moves into systemic circulation. Furthermore, the similarity of 2R3'R-SGM metabolism in humans and rats showed that the rat is a suitable animal for preclinical study. SN - 1520-6017 UR - https://www.unboundmedicine.com/medline/citation/30954525/Identification_of_Major_Esterase_Involved_in_Hydrolysis_of_Soft_Anticholinergic_(2R3'R-SGM)_Designed_From_Glycopyrrolate_in_Human_and_Rat_Tissues L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-3549(19)30213-8 DB - PRIME DP - Unbound Medicine ER -