RT Journal Article
SR Electronic
T1 Disposition and Metabolism of Darapladib, a Lipoprotein-Associated Phospholipase A2 Inhibitor, in Humans
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 415
OP 430
DO 10.1124/dmd.113.054486
VO 42
IS 3
A1 Mehul Dave
A1 Mike Nash
A1 Graeme C. Young
A1 Harma Ellens
A1 Mindy H. Magee
A1 Andrew D. Roberts
A1 Maxine A. Taylor
A1 Robert W. Greenhill
A1 Gary W. Boyle
YR 2014
UL http://dmd.aspetjournals.org/content/42/3/415.abstract
AB 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.