ABSTRACT
AIM: To evaluate the non-invasive collection of bile from healthy human subjects for the qualitative characterization of the biliary disposition of a drug, using spectrometric techniques. METHODS: Twenty subjects underwent non-invasive bile capture using a peroral string test (Entero-Test) device prior to and following a single oral dose of simvastatin (80 mg). The device, consisting of a weighted gelatin capsule containing a highly absorbent nylon string, was swallowed by each subject with the proximal end of the string taped to the face. Once the weighted string was judged to have reached the duodenum, gallbladder contraction was stimulated in order to release bile. The string was then retrieved via the mouth, and bile samples were analysed for drug-related material using spectrometric and spectroscopic techniques following solvent extraction. RESULTS: Numerous metabolites of simvastatin were detected, and the major metabolites were consistent with those reported from studies where bile was collected using invasive techniques from patients dosed with [(14) C]-simvastatin. CONCLUSIONS: The results from this study demonstrate the utility of deploying the Entero-Test in human studies to provide structural information on biliary metabolites. This can be readily applied in drug development studies, including those in the target patient population and may eliminate the need for more invasive sampling techniques.
Subject(s)
Anticholesteremic Agents/metabolism , Bile Acids and Salts/metabolism , Bile/metabolism , Pharmaceutical Preparations/metabolism , Simvastatin/metabolism , Adult , Anticholesteremic Agents/analysis , Bile Acids and Salts/analysis , Biliary Tract/metabolism , Chromatography, High Pressure Liquid/methods , Enterohepatic Circulation , Female , Humans , Magnetic Resonance Spectroscopy , Male , Pharmaceutical Preparations/analysis , Reagent Kits, Diagnostic , Reference Values , Simvastatin/analysisABSTRACT
8-Fluoroimidazo[1,2-a]pyridine has been established as a physicochemical mimic of imidazo[1,2-a]pyrimidine, using both in silico and traditional techniques. Furthermore, a novel synthesis of a 3,7-disubstituted-8-fluoroimidazopyridine 3 has been developed and the utility of the physicochemical mimicry has been demonstrated in an in vitro system. Here, the 8-fluoroimidazopyridine ring contained in ligand 3 acts as a bioisosteric replacement for imidazopyrimidine in the GABA(A) receptor modulator 2.
