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

Abstract

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.

Harnessing machine learning for development of microbiome therapeutics

“…29,30 Many reputable databases contain stool microbiome data, and the information should not be ignored as it can provide useful insights. 14,[31][32][33] It is, however, important to be aware of sampling methodology when conducting ML analysis to allow for valid interpretation.…”

“…Various drugs proven to be susceptible to metabolism by gut microbiota. 10,32,33,[172][173][174][175][176][177] e1872323-8…”

“…133 Over 180 orally administered drugs are now known to be metabolized by gut microbiota. 10,11,33,134,135 Microbiota drug metabolism can lead to significant inter-individual pharmacokinetic variability. 136 For example, a strain of Eggerthella lenta capable of inactivating the cardiac glycoside drug digoxin is estimated to inhabit the guts of 40% of the global population.…”

Simulated colonic fluid replicates the in vivo growth capabilities of Citrobacter rodentium mutants and highlights a critical role for the Cpx envelope stress response in mediating stressors encountered in the gastrointestinal tract

“…While HG-DMEM has been a frequent media used to induce virulence gene expression and mimic an in vivo environment prior to conducting animal model experiments, we chose to investigate the fitness of our mutants in a medium relevant to the conditions present in the colon by using SCF (31,32). SCF is a relatively uncommon media in individual pathogen fitness studies as in the past it has primarily been used for determining drug solubility and delivery systems which involve looking at the microbiota's affect on drug release (55,56). A more frequently used gastrointestinal fluid is simulated gastric fluid (SGF) which has been used to demonstrate acid-tolerance of pathogens like EPEC, EHEC, Vibrio cholerae, Listeria monocytogenes, and Salmonella (57)(58)(59)(60).…”

Progesterone Metabolism by Human and Rat Hepatic and Intestinal Tissue

“…The presence of bacteria is likely to further impact the stability of progesterone. Indeed, previous research within this group has demonstrated that progesterone undergoes a substantial amount of degradation in large intestinal contents [ 15 ]. It is, therefore, important to consider the metabolising abilities of the small intestine when preparing drugs for oral administration.…”