In Vivo Mechanisms of Intestinal Drug Absorption from Aprepitant Nanoformulations

Mol Pharm. 2017 Dec 4;14(12):4233-4242. doi: 10.1021/acs.molpharmaceut.7b00294. Epub 2017 Aug 10.


Over recent decades there has been an increase in the proportion of BCS class II and IV drug candidates in industrial drug development. To overcome the biopharmaceutical challenges associated with the less favorable properties of solubility and/or intestinal permeation of these substances, the development of formulations containing nanosuspensions of the drugs has been suggested. The intestinal absorption of aprepitant from two nanosuspensions (20 μM and 200 μM total concentrations) in phosphate buffer, one nanosuspension (200 μM) in fasted-state simulated intestinal fluid (FaSSIF), and one solution (20 μM) in FaSSIF was investigated in the rat single-pass intestinal perfusion model. The disappearance flux from the lumen (Jdisapp) was faster for formulations containing a total concentration of aprepitant of 200 μM than for those containing 20 μM, but was unaffected by the presence of vesicles. The flux into the systemic circulation (Japp) and, subsequently, the effective diffusion constant (Deff) were calculated using the plasma concentrations. Japp was, like Jdisapp, faster for the formulations containing higher total concentrations of aprepitant, but was also faster for those containing vesicles (ratios of 2 and 1.5). This suggests that aprepitant is retained in the lumen when presented as nanoparticles in the absence of vesicles. In conclusion, increased numbers of nanoparticles and the presence of vesicles increased the rate of transport and availability of aprepitant in plasma. This effect can be attributed to an increased rate of mass transport through the aqueous boundary layer (ABL) adjacent to the gut wall.

Keywords: aprepitant nanoformulations; aqueous boundary layer; fasted-state simulated intestinal fluid; intestinal drug absorption; nanosuspensions.

MeSH terms

  • Animals
  • Antiemetics / chemistry
  • Antiemetics / pharmacokinetics*
  • Aprepitant
  • Biological Availability
  • Biopharmaceutics / methods
  • Chemistry, Pharmaceutical
  • Intestinal Absorption*
  • Intestinal Mucosa / metabolism*
  • Male
  • Models, Animal
  • Morpholines / chemistry
  • Morpholines / pharmacokinetics*
  • Nanoparticles / chemistry
  • Perfusion / methods
  • Rats
  • Rats, Wistar
  • Solubility
  • Suspensions


  • Antiemetics
  • Morpholines
  • Suspensions
  • Aprepitant