Τίτλος:
Evaluating the clinical importance of bacterial degradation of therapeutic agents in the lower intestine of adults using adult fecal material
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Purpose: Optimize adult fecal material composition for evaluating the clinical importance of bacterial degradation of therapeutic agents in the lower intestine (distal small intestine, D-SI and proximal colon, P-COL). Evaluate the usefulness of optimized fecal material in the evaluation of bacterial degradation of five model highly permeable drugs: two nitroreductase substrates (nitrendipine and nimodipine), three drugs for which published data indicate no impact of bacterial degradation on in vivo performance (levodopa, budesonide and rivaroxaban) and one prodrug (sulfasalazine, an azoreductase substrate) from which a locally acting on the mucosa of the lower intestine drug is derived (mesalamine). Methods: 30 min and 95 min were used as point estimates of maximum bacterial degradation half-lives for bacterial degradation in D-SI or in P-COL, respectively, to be clinically important, i.e. for at least 20% reduction in absorption from D-SI or P-COL to occur. Optimization of fecal material was based on recently reported degradation profiles of metronidazole (a nitroreductase substrate) and olsalazine (an azoreductase substrate) in the lower intestine of healthy adults which are clinically important. Model compounds were tested in optimized fecal materials and data were evaluated vs. existing in vivo data in adults. Results: Simulated ileal bacteria (SIB) consisted of 5.5% (w/v) stools in normal saline and simulated colonic bacteria (SCoB) consisted of 8.3% (w/v) stools in normal saline. For all model compounds, data in SIB and SCoB were in line with available information in adults. [Degradation half-life in SIB/Degradation half-life in SCoB] ≈ [Stool content in SCoB/Stool content in SIB] ≈ 1.5, i.e. bacterial degradation in SIB could be predicted from bacterial degradation in SCoB. Conclusion: Data in SCoB only are useful for evaluating whether bacterial degradation in P-COL and in D-SI is likely to be clinically important for orally administered, highly permeable drugs or prodrugs which act locally after bacterial degradation. The usefulness of this approach in cases where enzymes other than nitroreductases or azoreductases are involved requires further confirmation. © 2018 Elsevier B.V.
Συγγραφείς:
Vertzoni, M.
Kersten, E.
van der Mey, D.
Muenster, U.
Reppas, C.
Περιοδικό:
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
Λέξεις-κλειδιά:
azo reductase; budesonide; carbidopa plus levodopa; levodopa; mesalazine; metronidazole; nimodipine; nitrendipine; nitroreductase; olsalazine; rivaroxaban; salazosulfapyridine; sodium chloride; sulfapyridine; drug, adult; area under the curve; Article; ascending colon; colon flora; descending colon; drug absorption; drug bioavailability; drug degradation; drug half life; enzyme activity; feces; human; intestine flora; male; normal human; priority journal; small intestine; bacterium; chemistry; intestine; metabolism; microbiology; middle aged, Adult; Bacteria; Feces; Gastrointestinal Microbiome; Humans; Intestines; Male; Middle Aged; Pharmaceutical Preparations
DOI:
10.1016/j.ejps.2018.09.019
