Li Yan, Fawcett J Paul, Zhang Hu, Tucker Ian G
School of Pharmacy, University of Otago, Dunedin, PO Box 913, New Zealand.
J Pharm Pharmacol. 2007 Apr;59(4):503-11. doi: 10.1211/jpp.59.4.0004.
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.
米托醌（甲磺酸盐米托Q(10)）是一种靶向线粒体的抗氧化剂，其制剂用于口服治疗神经退行性疾病。我们研究了米托Q(10)在Caco-2细胞单层中的吸收和代谢情况。米托Q(10)的细胞内蓄积量为添加的米托Q(10)总量的18% - 41%。细胞内的一些米托Q(10)被还原为米托喹醇，随后代谢为葡糖醛酸和硫酸盐结合物。米托Q(10)的转运具有极性，从基底外侧（BL）到顶端（AP）的表观渗透率（P(app)）（P(appBL-->AP)）大于从顶端到基底外侧（P(appAP-->BL)）的P(app)的2.5倍。在基底外侧存在4%牛血清白蛋白的情况下，P(appAP-->BL)值与对照相比增加了7倍。在分别存在100 microM维拉帕米、10 microM和30 microM环孢素的情况下，P(appBL-->AP)值分别降低了26%、31%和61%，而在存在30 microM环孢素的情况下，P(appAP-->BL)值增加了71%。30 microM环孢素和25 microM乳腺癌耐药蛋白（BCRP）抑制剂利血平分别显著降低了米托喹醇硫酸盐和米托喹醇葡糖醛酸结合物的顶端外排。这些结果表明，米托Q(10)的生物利用度可能受到细胞内代谢以及P-糖蛋白和BCRP作用的限制。然而，在接收侧存在牛血清白蛋白的情况下吸收性P(app)显著增加，这表明这些屏障功能在体内可能不太重要。
