Oleic acid-based formulation enables drug delivery of bRo5 compounds through intestinal lymphatic absorption

The beyond rule of 5 (bRo5) compounds, characterized by challenging properties such as low aqueous solubility and high lipophilicity, often exhibit limited oral bioavailability. In response, formulation technologies have been developed to support the absorption of bRo5 drugs via alternative pathways. Among them, intestinal lymphatic absorption may be one of the most relevant ones for highly lipophilic drugs, as first-pass metabolism is bypassed by the lymphatic flow and oral bioavailability might be increased. To understand how drug lipophilicity drives lymphatic absorption, we established in vitro and in vivo models and investigated oleic acid uptake via this absorption pathway. For in vivo research, a thoracic lymph duct-cannulated model was established in rats. The lymphatic uptake was modulated using oleic acid-dependent lipid vehicle-formulated lipophilic drugs, and its capacity was compared with drug concentrations from the one without oleic acid. For in vitro experiments, oleic acid and sodium taurocholate were used to induce chylomicron formation in the Caco-2 model. The surrogate effect of chylomicrons was assessed by correlating their compound permeability with the percentage of drug absorbed into rat lymph. In results, the Bcl-2 and Itraconazole compounds in lipid formulation showed higher lymph and plasma concentrations in vivo, compared to the same drug in non-lipid formulation. Lipophilic model drug permeability from chylomicron-induced Caco-2 strongly correlated with in vivo results for lymphatic absorption, similar to the outcomes observed using logP as a cutoff (>5) to identify drug propensity for lymphatic absorption. Altogether, this work demonstrated that lymphatic absorption is associated with drug lipophilicity and drug bioavailability can be influenced by formulation methods along with dietary lipids.