Skip to Content
MilliporeSigma
  • Profiling the role of deacylation-reacylation in the lymphatic transport of a triglyceride-mimetic prodrug.

Profiling the role of deacylation-reacylation in the lymphatic transport of a triglyceride-mimetic prodrug.

Pharmaceutical research (2014-12-03)
Sifei Han, Luojuan Hu, Tim Quach, Jamie S Simpson, Natalie L Trevaskis, Christopher J H Porter
ABSTRACT

Recent studies have demonstrated the potential for a triglyceride (TG) mimetic prodrug to promote the delivery of mycophenolic acid (MPA) to the lymphatic system. Here, the metabolic pathways that facilitate the lymphatic transport of the TG prodrug (1,3-dipalmitoyl-2-mycophenoloyl glycerol, 2-MPA-TG) were examined to better inform the design of next generation prodrugs. In vitro hydrolysis experiments in simulated intestinal conditions and in vivo rat lymphatic transport experiments were conducted in the presence and absence of orlistat and A922500 (inhibitors of lipolysis and TG re-esterification, respectively), to evaluate the importance of 2-MPA-TG digestion and re-esterification of 2-MPA-MG (the 2-monoglyceride derivative) in promoting lymphatic transport. 2-MPA-TG was rapidly hydrolysed to 2-MPA-MG on incubation with fresh bile and pancreatic fluid (BPF), but not in simulated gastric fluid, heat-inactivated BPF or BPF + orlistat. Orlistat markedly decreased lymphatic transport and systemic exposure of 2-MPA-TG derivatives suggesting that inhibition of pancreatic lipase hindered luminal digestion and absorption of the prodrug. A922500 also significantly decreased lymphatic transport of 2-MPA-TG but redirected MPA to the portal blood, suggesting that hindered re-acylation of 2-MPA-MG resulted in intracellular degradation. Incorporation into TG deacylation-reacylation pathways is a critical determinant of the utility of lymph directed TG-mimetic prodrugs.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Hydrochloric acid, 36.5-38.0%, BioReagent, for molecular biology
Sigma-Aldrich
Ammonium acetate, reagent grade, ≥98%
Supelco
Hydrochloric acid solution, volumetric, 0.1 M HCl (0.1N), endotoxin free
Sigma-Aldrich
Hydrochloric acid solution, 1.0 N, BioReagent, suitable for cell culture
Sigma-Aldrich
Ammonium acetate, 99.999% trace metals basis
Sigma-Aldrich
Ammonium formate, ≥99.995% trace metals basis
Sigma-Aldrich
Propylene glycol monomethyl ether acetate, ReagentPlus®, ≥99.5%
Sigma-Aldrich
Hydrogen chloride solution, 3 M in cyclopentyl methyl ether (CPME)
Sigma-Aldrich
Ammonium acetate, BioUltra, for molecular biology, ≥99.0%
Sigma-Aldrich
Ammonium acetate, BioXtra, ≥98%
Sigma-Aldrich
Ammonium formate, BioUltra, ≥99.0% (calc. based on dry substance, NT)
Supelco
Ammonium acetate, LiChropur, eluent additive for LC-MS
Supelco
Hydrogen chloride – ethanol solution, ~1.25 M HCl, for GC derivatization, LiChropur
Sigma-Aldrich
Acetonitrile solution, contains 0.1 % (v/v) formic acid, suitable for HPLC
Sigma-Aldrich
Ammonium acetate, for molecular biology, ≥98%
Supelco
Hydrogen chloride – 2-propanol solution, ~1.25 M HCl (T), for GC derivatization, LiChropur
Sigma-Aldrich
Ammonium acetate solution, BioUltra, for molecular biology, ~5 M in H2O
Supelco
Hydrogen chloride – methanol solution, ~1.25 m HCl (T), for GC derivatization, LiChropur
Sigma-Aldrich
Acetonitrile solution, contains 0.1 % (v/v) trifluoroacetic acid, suitable for HPLC
Sigma-Aldrich
Ammonium acetate solution, for molecular biology, 7.5 M
Sigma-Aldrich
Hydrochloric acid solution, ~6 M in H2O, for amino acid analysis
Sigma-Aldrich
Acetonitrile solution, contains 0.05 % (v/v) trifluoroacetic acid
Sigma-Aldrich
Serum Triglyceride Determination Kit, 1 kit sufficient for 250 tests
Sigma-Aldrich
Ammonium formate, SAJ first grade, ≥95.0%
Sigma-Aldrich
Hydrochloric acid solution, 1 M
Sigma-Aldrich
Ammonium acetate solution, 50 % (w/v), for copper determination
Sigma-Aldrich
Hydrochloric acid solution, 0.02 M
Sigma-Aldrich
Hydrochloric acid solution, 0.01 M
Sigma-Aldrich
Hydrochloric acid solution, 6 M
Sigma-Aldrich
Hydrogen chloride – ethanol solution, 0.1 M in ethanol