Monophosphate Derivatives of Luteolin and Apigenin as Efficient Precursors with Improved Oral Bioavailability in Rats

Abstract

Luteolin (Lut) and apigenin (Apn), flavones present in various edible plants, exhibit diverse antioxidant and pharmacological activities but have limited in vivo efficacy due to low water solubility and poor bioavailability. Here, we generated luteolin and apigenin monophosphate derivatives (LutPs and ApnPs) individually via microbial biotransformation. We then characterized their physicochemical properties and evaluated their in vitro and in vivo pharmacokinetics and bioavailability. Both LutPs and ApnPs showed enhanced solubility and dissolution and remained stable in simulated gastrointestinal conditions. Additionally, they efficiently reverted to parental forms via alkaline phosphatase in Caco-2 cells. Following oral administration in rats, LutPs and ApnPs exhibited higher plasma exposure to both aglycone and conjugated forms compared to Lut and Apn. Notably, the in vivo biotransformation of Apn to Lut was observed in all apigenin-related groups. Our study suggests that flavone monophosphates are effective alternatives with enhanced bioavailability, providing insights for the potential application of emerging bioactive nutraceuticals.