Progestogens Are Metabolized by the Gut Microbiota: Implications for Colonic Drug Delivery

被引:29
作者
Coombes, Zoe [1 ]
Yadav, Vipul [2 ]
McCoubrey, Laura E. [2 ]
Freire, Cristina [2 ,3 ]
Basit, Abdul W. [2 ]
Conlan, R. Steven [1 ]
Gonzalez, Deyarina [1 ]
机构
[1] Swansea Univ, Med Sch, Inst Life Sci 2, Swansea SA2 8PP, W Glam, Wales
[2] UCL, UCL Sch Pharm, Dept Pharmaceut, London WC1N 1AX, England
[3] Kuecept Ltd, Potters Bar EN6 1TL, Herts, England
基金
英国工程与自然科学研究理事会;
关键词
progesterone; medroxyprogesterone; levonorgestrel; large intestine metabolism; colonic stability; steroids; gastrointestinal bacteria; microbiome; MEDROXYPROGESTERONE ACETATE; BACTERIAL METABOLISM; IMPACT; STABILITY;
D O I
10.3390/pharmaceutics12080760
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Following oral administration, the bioavailability of progestogens is very low and highly variable, in part due to metabolism by cytochrome P450 enzymes found in the mucosa of the small intestine. Conversely, the mucosa in the colon contains much lower levels of cytochrome P450 enzymes, thus, colonic delivery of progestogens may be beneficial. Microbiota in the colon are known to metabolize a great number of drugs, therefore, it is important to understand the stability of these hormones in the presence of colonic flora before developing formulations. The aim of this study was to investigate the stability of three progestogens: progesterone, and its two synthetic analogues, medroxyprogesterone acetate (MPA) and levonorgestrel (LNG), in the presence of human colonic microbiota. Progesterone, MPA, and LNG were incubated in mixed fecal inoculum (simulated human colonic fluid) under anerobic conditions. Progesterone was completely degraded after 2 h, whereas levels of MPA and LNG were still detectable after 24 h. The half-lives of progesterone, MPA, and LNG in fecal inoculum were 28, 644, and 240 min, respectively. This study describes the kinetics of colonic microbial metabolism of these hormones for the first time. MPA and LNG show promise for delivery to the colon, potentially improving pharmacokinetics over current oral delivery methods.
引用
收藏
页码:1 / 10
页数:10
相关论文
共 49 条
[41]   OPTICORE™, an innovative and accurate colonic targeting technology [J].
Varum, Felipe ;
Freire, Ana Cristina ;
Bravo, Roberto ;
Basit, Abdul W. .
INTERNATIONAL JOURNAL OF PHARMACEUTICS, 2020, 583
[42]   Impact of host and environmental factors on β-glucuronidase enzymatic activity: implications for gastrointestinal serotonin [J].
Walsh, Jacinta ;
Olavarria-Ramirez, Loreto ;
Lach, Gilliard ;
Boehme, Marcus ;
Dinan, Timothy G. ;
Cryan, John F. ;
Griffin, Brendan T. ;
Hyland, Niall P. ;
Clarke, Gerard .
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 2020, 318 (04) :G816-G826
[43]   Drug-gut microbiota interactions: implications for neuropharmacology [J].
Walsh, Jacinta ;
Griffin, Brendan T. ;
Clarke, Gerard ;
Hyland, Niall P. .
BRITISH JOURNAL OF PHARMACOLOGY, 2018, 175 (24) :4415-4429
[44]   Stability of peptide drugs in the colon [J].
Wang, Jie ;
Yadav, Vipul ;
Smart, Alice L. ;
Tajiri, Shinichiro ;
Basit, Abdul W. .
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, 2015, 78 :31-36
[45]  
WATKINS PB, 1992, GASTROENTEROL CLIN N, V21, P511
[46]   Gastrointestinal stability of therapeutic anti-TNF α IgG1 monoclonal antibodies [J].
Yadav, Vipul ;
Varum, Felipe ;
Bravo, Roberto ;
Furrer, Esther ;
Basit, Abdul W. .
INTERNATIONAL JOURNAL OF PHARMACEUTICS, 2016, 502 (1-2) :181-187
[47]   Colonic bacterial metabolism of corticosteroids [J].
Yadav, Vipul ;
Gaisford, Simon ;
Merchant, Hamid A. ;
Basit, Abdul W. .
INTERNATIONAL JOURNAL OF PHARMACEUTICS, 2013, 457 (01) :268-274
[48]   Metabolic Profiling and Cytochrome P450 Reaction Phenotyping of Medroxyprogesterone Acetate [J].
Zhang, Jiang-Wei ;
Liu, Yong ;
Zhao, Jiu-Yang ;
Wang, Li-Ming ;
Ge, Guang-Bo ;
Gao, Yang ;
Li, Wei ;
Liu, Hong-Tao ;
Liu, Hui-Xin ;
Zhang, Yan-Yan ;
Sun, Jie ;
Yang, Ling .
DRUG METABOLISM AND DISPOSITION, 2008, 36 (11) :2292-2298
[49]   Mapping human microbiome drug metabolism by gut bacteria and their genes [J].
Zimmermann, Michael ;
Zimmermann-Kogadeeva, Maria ;
Wegmann, Rebekka ;
Goodman, Andrew L. .
NATURE, 2019, 570 (7762) :462-+