Mitoquinone (MitoQ(10) mesylate) is a mitochondria-targeted antioxidant formulated for oral administration in the treatment of neurodegenerative diseases. We have investigated the absorption and metabolism of MitoQ(10) in Caco-2 cell monolayers. The intracellular accumulation of MitoQ(10) was 18-41% of the total amount of MitoQ(10) added. Some of the intracellular MitoQ(10) was reduced to mitoquinol and subsequently metabolized to glucuronide and sulfate conjugates. Transport of MitoQ(10) was polarized with the apparent permeability (P(app)) from basolateral (BL) to apical (AP) (P(appBL-->AP)) being >2.5-fold the P(app) from apical to basolateral (P(appAP-->BL)). In the presence of 4% bovine serum albumin on the basolateral side, the P(appAP-->BL) value increased 7-fold compared with control. The P(appBL-->AP) value decreased by 26, 31 and 61% in the presence of verapamil 100 microM, ciclosporin 10 and 30 microM, respectively, whereas the P(appAP-->BL) value increased 71% in the presence of ciclosporin 30 microM. Apical efflux of mitoquinol sulfate and mitoquinol glucuronide conjugates was significantly decreased by ciclosporin 30 microM and the breast cancer receptor protein (BCRP) inhibitor, reserpine 25 microM, respectively. These results suggested that the bioavailability of MitoQ(10) may be limited by intracellular metabolism and the action of P-glycoprotein and BCRP. However, the dramatic increase in absorptive P(app) in the presence of bovine serum albumin on the receiver side suggests these barrier functions may be less significant in-vivo.