Table 3:
SCFA prodrugs
| SCFA prodrugs tested in vivo | |||
|---|---|---|---|
| Structurea | Name(s) | Species/disease model (route of admin., dose, dosage form) | Key findings (ClinicalTrials.gov identifier and/or references) |
|
Tributyrin (TB) | Healthy mice (p.o.) | Improved PK characteristics compared to i.v. bolus sodium butyrate. Similar plasma butyrate AUC to p.o. sodium butyrate, suggesting complete hydrolysis in GI tract (Egorin et al., 1999). |
| Preclinical LPS-, HFD- and ethanol-induced liver injury models (p.o. 1–2 g/kg/d or wk) | Transiently elevates butyrate conc. in hepatic portal vein, reduces liver inflammation (Donde et al., 2020; Miyoshi et al., 2011, 2015; Sato et al., 2020; Singhal et al., 2021; Vinolo et al., 2012). | ||
| Clinical trials in patients with solid tumors (p.o. 400–600 mg/kg/d, hard gelatin capsules) | Low/variable plasma butyrate exposure, limited efficacy, side effects ranging from grade 1 to grade 3 (NCT00002677, Conley et al., 1998, Edelman et al., 2003). | ||
| Healthy rats (p.o, cholesterol-based lipid emulsion) | Increased plasma butyrate AUC compared to p.o. free TB, enhanced absorption and increased p.o. bioavailability (Su et al., 2006). | ||
|
Pivaloyloxymethyl butyrate (AN-9, Pivanex) | Clinical trials in patients with solid tumors (i.v. infusion, ≤90 mg/kg/d, Intralipid® 20% emulsion) | Modest outcomes including disease stabilization in some patients, no dose-limiting toxicity (Patnaik et al., 2002; Reid et al., 2004). |
| Spinal muscular atrophy mouse model (p.o., 400 mg/kg/d, Intralipid® 20% emulsion) | Increased survival and growth rate (Edwards & Butchbach, 2016). | ||
|
Butyroyloxymethyl diethylphosphate (AN-7) | Tumor-bearing mice (p.o., 50 mg/kg 3x/wk) | High oral bioavailability, inhibited tumor growth and increased survival without adverse events (Rephaeli et al., 2005, 2006). More potent than AN-9 (Tarasenko et al., 2008). |
| Ischemic cardiac injury model (p.o.,25 mg/kg in mice, 15 mg/kg in rats) | Selectively affects cardiomyocytes to confer improved cardiac recovery from ischemia and reperfusion performed ex-vivo (Kessler-Icekson et al., 2012). | ||
| Healthy rabbits (i.v.) | Greater mean residence times than i.v. bolus arginine butyrate, limited toxicity (Pouillart, Ronco, et al., 1992). | ||
|
6-O-[butanoyl…] (MAG-6But) | Tumor-bearing mice (i.p., 3×10−6 M ~ 0.468 ug/mL per mouse) | Extended survival times compared to i.p. arginine butyrate (Pouillart et al., 1991). |
| Mice infected with encephalomyocarditis virus (i.p., 3×10−6 M ~ 0.468 ug/mL per mouse) | More effectively protected mice against infection than i.p. arginine butyrate (Pouillart, Cerutti, et al., 1992, p. 11). | ||
|
N-(1-carbamoyl-2-phenyl-ethyl) butyramide (FBA) | Healthy mice (p.o) | Similar serum butyrate PK compared to p.o. sodium butyrate, suggesting complete butyrate release in GI tract (Russo et al., 2021). |
| HFD-fed mice and rats (p.o., 127.5 mg/kg/d) | Similar or improved efficacy compared to sodium butyrate, depending on the outcome measure (Mattace Raso et al., 2013; Mollica et al., 2017). | ||
| Mice with DSS-induced colitis (p.o., 42.5 mg/kg/d) and mice with antibiotic-induced intestinal and liver injury (p.o., 637.5 mg/kg/d) | Improved intestinal barrier functions, reduced intestinal and liver inflammation, modulated microbiome (Simeoli et al., 2017; Lama et al., 2019). | ||
|
SCFA-Azithromycin esters (PAE and BAE) | Healthy mice (i.v. and p.o.) | High distribution into intestine, liver, and other tissues. Stable during their transit through the stomach, hydrolyzed in GI tract and liver. Some pAe metabolites detected in brain (Straß et al., 2021). |
|
2-seryl butyrate (SerBut) | Healthy mice (p.o.) | Increased butyrate levels in plasma and various tissues, notably the spinal cord and brain, compared to p.o. sodium butyrate (Cao, Budina, Raczy, et al., 2023). |
| Structures below | pMan-But and pMan-PhBut | T2D (db/db) excisional wound mouse model (topical, 1% hyaluronic acid + pMan-But or - PhBut (10% butyrate w/w)) | pMan-But, but not pMan-PhBut, induced pro-regenerative shifts in cytokines and chemokines in the wound microenvironment and accelerated wound healing (Lauterbach et al., 2023). |
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| SCFA prodrugs tested only in vitro | |||
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| CIA mouse model of rheumatoid arthritis (p.o., 25 mg/mouse once daily) and EAE mouse model of multiple sclerosis (p.o., 100 mM SerBut in DW + 24 mg SerBut/mouse post-EAE induction once or twice daily) | Ameliorated disease progression, promoted anti-inflammatory immune cell phenotypes. Did not interfere with global immune response to vaccination (Cao, Budina, Raczy, et al., 2023). | ||
a:
chemical structures generated using ChemDraw® (PerkinElmer).