Use of the entero-test, a novel approach for the noninvasive capture of biliary metabolites in dogs.
Preclinical information on the biliary metabolites of a drug candidate is typically obtained through the collection of bile after surgical cannulation of the bile duct. In this study, we describe a novel approach using the Entero-Test, a simple device that facilitates the noninvasive sampling of duodenal bile. The Entero-Test was used to collect bile from six fasted dogs that had been dosed either orally with simvastatin (SV) or intravenously with simvastatin hydroxy acid (SVA), compounds that have been previously reported to undergo extensive metabolism and biliary secretion in the dog. The devices, consisting of a weighted gelatin capsule containing 90 cm of a highly absorbent nylon string, were swallowed by each dog with the proximal end of the string taped to the animal's face. Once the weighted string had reached the duodenum, gallbladder contraction was stimulated to release bile. Each bile-stained string was then retrieved via the mouth and, after solvent extraction, samples were analyzed for drug-related material by ultraperformance liquid chromatography-mass spectrometry and NMR spectroscopy. Numerous metabolites of SV and SVA were observed, and, in general, the major metabolites have been reported previously from studies with bile duct-cannulated animals dosed with [14C]SV or [14C]SVA. The results from this study demonstrate the utility of deploying the Entero-Test in absorption, distribution, metabolism, and elimination studies to provide information on the nature of biliary metabolites, which, on occasion, may be sufficient to negate the need for more invasive sampling techniques. The benefits and limitations of the technique are discussed.
Guiney
W J
WJ
Toxicokinetics and Biotransformation, PCD DMPK Department, GlaxoSmithKline, Park Road, Ware, Hertfordshire SG120DP, UK. william.guiney@gsk.com
Beaumont
C
C
Thomas
S R
SR
D000818:Animals; D001646:Bile / Q000737:chemistry / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003938:Diagnostic Techniques, Digestive System / Q000009:adverse effects / Q000295:instrumentation*; D004285:Dogs; D004386:Duodenum / Q000737:chemistry / Q000378:metabolism*; D020719:Glucuronides / Q000032:analysis / Q000378:metabolism; D006900:Hydroxylation; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010084:Oxidation-Reduction; D004364:Pharmaceutical Preparations / Q000032:analysis / Q000378:metabolism*; D019821:Simvastatin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization
D020719:Glucuronides; D004364:Pharmaceutical Preparations; C532833:simvastatin hydroxyacid; D019821:Simvastatin