Abstract
Esculetin-7-O-glucuronide (ET-G) and 4-Methylesculetin-7-O-glucuronide (4-ME-G) are the main glucuronide of esculetin (ET) and 4-methylesculetin (4-ME), respectively. The disposition mediated by efflux transporters for glucuronide has significant influence on the pharmacokinetic profile and efficacy of bioactive compounds. In the current study, transporter gene knockout mice and Caco-2 cells were used to explore the effects of breast cancer resistance protein (BCRP) and multidrug resistance protein 2 (MRP2) on the disposition of ET-G and 4-ME-G. After oral or intravenous administration of ET and 4-ME, the AUC0-∞ values of ET, 4-ME, and their glucuronides (ET-G and 4-ME-G) were remarkably and significantly increased in most Bcrp1-/- and Mrp2-/- mice compared with those in wild-type FVB mice (P < 0.05). These results were accompanied with a significant increase of Cmax values (P < 0.05). In Caco-2 monolayers, the efflux and clearance rates of ET-G and 4-ME-G were markedly reduced by the BCRP inhibitor Ko143 and MRP2 inhibitor MK571 on the apical side (P < 0.05). In an intestinal perfusion study, the excretion of ET-G was significantly decreased in perfusate and increased in plasma in Bcrp1-/- mice compared with those in wild-type FVB mice (P < 0.05). The 4-ME-G concentration was also decreased in the bile in transporter gene-knockout mice. ET and 4-ME showed good permeability in both Caco-2 momolayers (P*app ≥ 0.59 x 10−5 cm/s) and duodenum (P*app ≥ 1.81). In conclusion, BCRP and MRP2 are involved in excreting ET-G and 4-ME-G. ET and 4-ME are likely absorbed via passive diffusion in the intestines.
- cell models
- drug absorption
- drug delivery
- efflux transporters (P-gp, BCRP, MRP, MATE, BSEP, etc)
- glucuronidation/UDP-glucuronyltransferases/UGT
- mass spectrometry/MS
- membrane permeability
- metabolite disposition
- pharmacokinetics
- UPLC
- The American Society for Pharmacology and Experimental Therapeutics