Disposition and metabolism of darapladib, a lipoprotein-associated phospholipase A2 inhibitor, in humans.

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.

Determination of surface areas, volumes, and lengths of cynomolgus monkey nasal cavities by ex vivo magnetic resonance imaging.

We have used high-resolution three-dimensional magnetic resonance imaging (MRI) to measure the surface area, volume, and length of the nasal cavities of cynomolgus monkeys (10 male, six female) over a range of body weights (1.9-5.3 kg, mean 2.9 kg) and ages (8-45 months, mean 30.0 months). The measurements were carried out ex vivo on formalin-fixed, decalcified nasal cavities filled with water. Mean (standard deviation) values were 30.2 (7.2) cm(2), 2.33 (0.65) cm(3), and 3.34 (0.44) cm, respectively. Linear regression least squares best fits provide the following empirical relationships: Nasal cavity surface area (SA, cm(2)) as a function of body weight (BW, kg): SA = 15.1 + 5.1(BW), R = 0.84 Nasal cavity volume (V, cm(3)) as a function of body weight: V = 1.15 + 0.4(BW), R = 0.74 Nasal cavity length (L, cm) as a function of body weight: L = 2.43 + 0.31(BW), R = 0.84 The left and right sides of the cavity were symmetrical in both males and females and showed little anatomical variation between individuals. The perimeter of the nasal cavity was maximal at about 60% of its extent from the nares. These data can aid in extrapolating nasal dosimetric exposure indices from cynomolgus monkeys (1.9-5.3 kg) to other species.

Longitudinal magnetic resonance imaging quantitation of rat liver regeneration after partial hepatectomy.

This report demonstrates the advantages of using a noninvasive soft tissue imaging technique--magnetic resonance imaging (MRI)--to monitor liver regeneration after 70% partial hepatectomy in the rat in a longitudinal manner. Six animals were scanned prior to and on 6 subsequent occasions up to 9 days after surgical removal of the median and left lateral lobes. Within the observed time frame liver volumes were restored to approximately 88% of presurgery values. Final liver volumes correlated well with postmortem liver weights (R = 0.93). Regeneration is well-quantified empirically by a 4 parameter logistic equation: % Regeneration = 84 - (84/(1 + (Days/2.31)(2.34))) The rate of regeneration was maximal at 1.5 days, which coincided with the maximum increase of Mitotic Index--a measure of cell proliferation, determined in a subsequent study. Pre- and postpartial hepatectomy measurements remove two potentially confounding unknowns--the presurgery liver volume, and the amount of liver actually excised. 3D reconstructions of the liver effectively illustrate the morphological changes associated with the procedure, and the regrowth of liver tissue.