Bergagnini-Kolev Mackenzie C, Hebert Mary F, Easterling Thomas R, Lin Yvonne S
Department of Pharmaceutics (M.C.B.-K.,Y.S.L.), Department of Obstetrics and Gynecology (M.F.H., T.R.E.), and Department of Pharmacy (M.F.H.), University of Washington, Seattle, Washington.
Department of Pharmaceutics (M.C.B.-K.,Y.S.L.), Department of Obstetrics and Gynecology (M.F.H., T.R.E.), and Department of Pharmacy (M.F.H.), University of Washington, Seattle, Washington
Drug Metab Dispos. 2017 Mar;45(3):325-329. doi: 10.1124/dmd.116.073841. Epub 2017 Jan 9.
N-methylnicotinamide (1-NMN) has been investigated as an endogenous probe for the renal transporter activity of organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins 1 and 2-K (MATE1 and MATE2-K). As pregnancy increased the renal secretion of metformin, a substrate for OCT2, MATE1, and MATE2-K, we hypothesized that the renal secretion of 1-NMN would be similarly affected. Blood and urine samples collected from women prescribed metformin for type 2 diabetes, gestational diabetes, and polycystic ovarian syndrome during early, mid, and late pregnancy ( = 34 visits) and postpartum ( = 14 visits) were analyzed for 1-NMN using liquid chromatography-mass spectrometry. The renal clearance and secretion clearance, using creatinine clearance to correct for glomerular filtration, were estimated for 1-NMN and correlated with metformin renal clearance. 1-NMN renal clearance was higher in both mid (504 ± 293 ml/min, < 0.01) and late pregnancy (557 ± 305 ml/min, < 0.01) compared with postpartum (240 ± 106 ml/min). The renal secretion of 1-NMN was 3.5-fold higher in mid pregnancy (269± 267, < 0.05) and 4.5-fold higher in late pregnancy compared with postpartum (342 ± 283 versus 76 ± 92 ml/min, < 0.01). Because creatinine is also a substrate of OCT2, MATE1, and MATE2-K, creatinine clearance likely overestimates filtration clearance, whereas the calculated 1-NMN secretion clearance is likely underestimated. Metformin renal clearance and 1-NMN renal clearance were positively correlated (r = 0.68, < 0.0001). 1-NMN renal clearance increases during pregnancy due to increased glomerular filtration and net secretion by renal transporters.
N-甲基烟酰胺（1-NMN）已被作为一种内源性探针，用于研究有机阳离子转运体2（OCT2）以及多药和毒素外排蛋白1和2-K（MATE1和MATE2-K）的肾脏转运活性。由于妊娠会增加二甲双胍（一种OCT2、MATE1和MATE2-K的底物）的肾脏分泌，我们推测1-NMN的肾脏分泌也会受到类似影响。我们使用液相色谱-质谱法分析了从患有2型糖尿病、妊娠期糖尿病和多囊卵巢综合征的女性在妊娠早期、中期和晚期（共34次就诊）以及产后（共14次就诊）开具二甲双胍处方时采集的血液和尿液样本中的1-NMN。使用肌酐清除率校正肾小球滤过，估算了1-NMN的肾脏清除率和分泌清除率，并将其与二甲双胍的肾脏清除率相关联。与产后（240±106 ml/min）相比，妊娠中期（504±293 ml/min，P<0.01）和晚期（557±305 ml/min，P<0.01）的1-NMN肾脏清除率均更高。与产后相比，妊娠中期1-NMN的肾脏分泌高出3.5倍（269±267，P<0.05），妊娠晚期高出4.5倍（342±283对76±92 ml/min，P<0.01）。由于肌酐也是OCT2、MATE1和MATE2-K的底物，肌酐清除率可能高估了滤过清除率，而计算出的1-NMN分泌清除率可能被低估。二甲双胍的肾脏清除率与1-NMN的肾脏清除率呈正相关（r = 0.68，P<0.0001）。由于肾小球滤过增加以及肾脏转运体的净分泌增加，妊娠期间1-NMN的肾脏清除率升高。
