Using lipid-based drug delivery systems (LbDDS) is an efficient strategy to enhance the low oral bioavailability of poorly water-soluble drugs. Here the oral absorption of fenofibrate (FF) from LbDDS in rats was investigated in pharmacokinetic, in vitro lipolysis, and SPECT/CT in vivo imaging studies. The investigated formulations were soybean oil solution (SBO), a mixture of soybean oil and monoacyl phosphatidylcholine (MAPC) (SBO-MAPC), self-nanoemulsifying drug delivery systems with and without MAPC (SNEDDS-MAPC and SNEDDS, respectively), and an aqueous suspension (SUSP) as a reference. Oral bioavailability of the LbDDS ranged from 27 to 35%. A two-step in vitro lipolysis model simulating rat gastro-intestinal digestion provided in vitro FF solubilisation data to understand oral absorption. During the in vitro lipolysis, most FF was undissolved for SUSP and distributed into the poorly dispersed oil phase for SBO. For the SNEDDS without MAPC, practically all FF solubilised into the aqueous phase during the dispersion and digestion. Adding MAPC to SBO enhanced the dispersion of the oil phase into the digestion media while adding MAPC to SNEDDS resulted in a distribution of 29% of FF into the oil phase at the beginning of in vitro lipolysis. FF distribution into both oil and aqueous phases explained the higher and prolonged oral absorption of LbDDS containing MAPC. To elucidate the relatively low bioavailability of all formulations, FF and triolein were labeled with 123I and 125I, respectively, to study the biodistribution of drug and lipid excipients in a dual isotope SPECT/CT in vivo imaging study. The concentration of radiolabeled drug as a function of time in the heart correlated to the plasma curves. A significant amount of radiolabeled drug and lipids (i.e., 28-59% and 24-60% of radiolabeled drug and lipids, respectively) was observed in the stomach at 24 h post administration, which can be linked to the low bioavailability of the formulations. The current study for the first time combined in vitro lipolysis and dual isotope in vivo imaging to find the root cause of different fenofibrate absorption profiles from LbDDS and an aqueous suspension.
Keywords: Biodistribution; Dual radioisotope imaging; Fenofibrate; Lipid-based drug delivery systems; Monoacyl phosphatidylcholine; Pharmacokinetics; SPECT/CT; Surfactant; in vitro lipolysis.
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