Breast Cancer Resistance Protein and Multidrug Resistance Protein 2 Regulate the Disposition of Acacetin Glucuronides.

ABSTRACT

PURPOSE: To determine the mechanism responsible for acacetin glucuronide transport and the bioavailability of acacetin. METHODS: Area under the curve (AUC), clearance (CL), half-life (T1/2) and other pharmacokinetic parameters were determined by the pharmacokinetic model. The excretion of acacetin glucuronides was evaluated by the mouse intestinal perfusion model and the Caco-2 cell model. RESULTS: In pharmacokinetic studies, the bioavailability of acacetin in FVB mice was 1.3%. Acacetin was mostly exposed as acacetin glucuronides in plasma. AUC of acacetin-7-glucuronide (Aca-7-Glu) was 2-fold and 6-fold higher in Bcrp1 (-/-) mice and Mrp2 (-/-) mice, respectively. AUC of acacetin-5-glucuronide (Aca-5-Glu) was 2-fold higher in Bcrp1 (-/-) mice. In mouse intestinal perfusion, the excretion of Aca-7-Glu was decreased by 1-fold and 2-fold in Bcrp1 (-/-) and Mrp2 (-/-) mice, respectively. In Caco-2 cells, the efflux rates of Aca-7-Glu and Aca-5-Glu were significantly decreased by breast cancer resistance protein (BCRP) inhibitor Ko143 and multidrug resistance protein 2 (MRP2) inhibitor LTC4. The use of these inhibitors markedly increased the intracellular acacetin glucuronide content. CONCLUSIONS: BCRP and MRP2 regulated the in vivo disposition of acacetin glucuronides. The coupling of glucuronidation and efflux transport was probably the primary reason for the low bioavailability of acacetin.