title: Disposition and metabolism of darapladib, a lipoprotein-associated phospholipase A2 inhibitor, in humans.
abstract: The absorption, metabolism, and excretion of darapladib, a novel inhibitor of lipoprotein-associated phospholipase A2, was investigated in healthy male subjects using [(14)C]-radiolabeled material in a bespoke study design. Disposition of darapladib was compared following single i.v. and both single and repeated oral administrations. The anticipated presence of low circulating concentrations of drug-related material required the use of accelerator mass spectrometry as a sensitive radiodetector. Blood, urine, and feces were collected up to 21 days post radioactive dose, and analyzed for drug-related material. The principal circulating drug-related component was unchanged darapladib. No notable metabolites were observed in plasma post-i.v. dosing; however, metabolites resulting from hydroxylation (M3) and N-deethylation (M4) were observed (at 4%-6% of plasma radioactivity) following oral dosing, indicative of some first-pass metabolism. In addition, an acid-catalyzed degradant (M10) resulting from presystemic hydrolysis was also detected in plasma at similar levels of ∼5% of radioactivity post oral dosing. Systemic exposure to radioactive material was reduced within the repeat dose regimen, consistent with the notion of time-dependent pharmacokinetics resulting from enhanced clearance or reduced absorption. Elimination of drug-related material occurred predominantly via the feces, with unchanged darapladib representing 43%-53% of the radioactive dose, and metabolites M3 and M4 also notably accounting for ∼9% and 19% of the dose, respectively. The enhanced study design has provided an increased understanding of the absorption, distribution, metabolism and excretion (ADME) properties of darapladib in humans, and substantially influenced future work on the compound.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics (M.D., M.N., G.C.Y., A.D.R., M.A.T., G.W.B.) and Department of Safety Assessment (R.W.G.), GlaxoSmithKline Research & Development, Ware, United Kingdom, and Department of Drug Metabolism and Pharmacokinetics (H.E.) and Clinical Pharmacology, Modeling and Simulation (M.H.M.), GlaxoSmithKline Research & Development, Upper Merion, Philadelphia.
authors.forename: Mehul
authors.initials: M
authors.lastname: Dave
authors.forename: Mike
authors.initials: M
authors.lastname: Nash
authors.forename: Graeme C
authors.initials: GC
authors.lastname: Young
authors.forename: Harma
authors.initials: H
authors.lastname: Ellens
authors.forename: Mindy H
authors.initials: MH
authors.lastname: Magee
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Roberts
authors.forename: Maxine A
authors.initials: MA
authors.lastname: Taylor
authors.forename: Robert W
authors.initials: RW
authors.lastname: Greenhill
authors.forename: Gary W
authors.initials: GW
authors.lastname: Boyle
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000328:Adult; D001547:Benzaldehydes / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D001711:Biotransformation; D002247:Carbon Isotopes; D002250:Carbon Radioisotopes; D005243:Feces / Q000737:chemistry; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D015394:Molecular Structure; D010091:Oximes / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D064801:Phospholipase A2 Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
chemical_list: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D001547:Benzaldehydes; D002247:Carbon Isotopes; D002250:Carbon Radioisotopes; D010091:Oximes; D064801:Phospholipase A2 Inhibitors; C529040:darapladib; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides