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Research ArticleArticle

Disposition and Metabolism of Darapladib, a Lipoprotein-Associated Phospholipase A2 Inhibitor, in Humans

Mehul Dave, Mike Nash, Graeme C. Young, Harma Ellens, Mindy H. Magee, Andrew D. Roberts, Maxine A. Taylor, Robert W. Greenhill and Gary W. Boyle
Drug Metabolism and Disposition March 2014, 42 (3) 415-430; DOI: https://doi.org/10.1124/dmd.113.054486
Mehul Dave
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
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Mike Nash
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
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Graeme C. Young
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
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Harma Ellens
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
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Mindy H. Magee
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
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Andrew D. Roberts
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
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Maxine A. Taylor
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
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Robert W. Greenhill
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
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Gary W. Boyle
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
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Abstract

The absorption, metabolism, and excretion of darapladib, a novel inhibitor of lipoprotein-associated phospholipase A2, was investigated in healthy male subjects using [14C]-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.

Footnotes

    • Received September 6, 2013.
    • Accepted December 30, 2013.
  • dx.doi.org/10.1124/dmd.113.054486.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (3)
Drug Metabolism and Disposition
Vol. 42, Issue 3
1 Mar 2014
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Research ArticleArticle

Disposition and Metabolism of Darapladib in Humans

Mehul Dave, Mike Nash, Graeme C. Young, Harma Ellens, Mindy H. Magee, Andrew D. Roberts, Maxine A. Taylor, Robert W. Greenhill and Gary W. Boyle
Drug Metabolism and Disposition March 1, 2014, 42 (3) 415-430; DOI: https://doi.org/10.1124/dmd.113.054486

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Research ArticleArticle

Disposition and Metabolism of Darapladib in Humans

Mehul Dave, Mike Nash, Graeme C. Young, Harma Ellens, Mindy H. Magee, Andrew D. Roberts, Maxine A. Taylor, Robert W. Greenhill and Gary W. Boyle
Drug Metabolism and Disposition March 1, 2014, 42 (3) 415-430; DOI: https://doi.org/10.1124/dmd.113.054486
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