Szabó Kitti, Nagy Zoltán, Juhász Viktória, Zolnerciks Joseph K, Csorba Attila, Tímár Zoltán, Molnár Éva, Pádár Petra, Johnson William, Beéry Erzsébet, Krajcsi Péter
SOLVO Biotechnology, 2 Gyár utca, Budaörs 2040, Hungary; SOLVO Biotechnology, 52 Közép fasor, Szeged 6726, Hungary.
SOLVO Biotechnology, 2 Gyár utca, Budaörs 2040, Hungary.
Drug Metab Pharmacokinet. 2017 Jun;32(3):165-171. doi: 10.1016/j.dmpk.2016.08.005. Epub 2016 Aug 26.
The purpose of this study was to characterize the uptake of carnitine, the physiological substrate, and the uptake of 3-(2,2,2-trimethylhydrazinium)propionate, a consensus substrate by rat Octn2 and human OCTN2 transporters as well as to characterize drug-mediated inhibition of l-carnitine uptake by the rat and human orthologs overexpressed in CHO-K1 cells. l-carnitine and 3-(2,2,2-trimethylhydrazinium)propionate were found to be a lower affinity substrate for rat Octn2 (K = 32.66 ± 5.11 μM and 23.62 ± 4.99 μM respectively) than for human OCTN2 (K = 3.08 ± 0.74 μM and 7.98 ± 0.63 μM). The intrinsic clearance (CL) value for carnitine was higher for the human than for the rat transporter (22.82 ± 5.57 ml/minmg vs 4.008 ± 0.675 ml/minmg). For 3-(2,2,2-trimethylhydrazinium)propionate, in contrast, the CL value for rat Octn2 was higher than for human OCTN2 (323.9 ± 72.8 ml/minmg vs 65.11 ± 5.33 ml/minmg). Furthermore, many pharmacologically important drugs were shown to affect l-carnitine transport by Octn2/OCTN2. The correlation between the IC datasets for the rat and human transporter resulted in an r value of 0.47 (p > 0.05). However, the greatest difference was less than seven-fold and 13 of 15 compounds yielded a difference less than 3-fold. Thus, the transporters from these two species showed an overlapping but somewhat different substrate and inhibitor specificity.
本研究的目的是表征肉碱（一种生理底物）以及3-(2,2,2-三甲基肼基)丙酸酯（一种公认的底物）被大鼠Octn2和人类OCTN2转运体摄取的情况，同时表征在CHO-K1细胞中过表达的大鼠和人类直系同源物对左旋肉碱摄取的药物介导抑制作用。结果发现，与人类OCTN2相比，肉碱和3-(2,2,2-三甲基肼基)丙酸酯对大鼠Octn2的亲和力较低（K分别为32.66±5.11μM和23.62±4.99μM，而人类OCTN2的K分别为3.08±0.74μM和7.98±0.63μM）。人类转运体对肉碱的内在清除率（CL）值高于大鼠转运体（22.82±5.57ml/minmg对4.008±0.675ml/minmg）。相比之下，对于3-(2,2,2-三甲基肼基)丙酸酯，大鼠Octn2的CL值高于人类OCTN2（323.9±72.8ml/minmg对65.11±5.33ml/minmg）。此外，许多具有药理学重要性的药物被证明会影响Octn2/OCTN2对左旋肉碱的转运。大鼠和人类转运体的IC数据集之间的相关性导致r值为0.47（p>0.05）。然而，最大差异小于7倍，15种化合物中有13种的差异小于3倍。因此，这两个物种的转运体表现出重叠但又有所不同的底物和抑制剂特异性。
