title: Pregnancy Increases the Renal Secretion of N1-methylnicotinamide, an Endogenous Probe for Renal Cation Transporters, in Patients Prescribed Metformin.
abstract: N1-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 (n= 34 visits) and postpartum (n= 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,P< 0.01) and late pregnancy (557 ± 305 ml/min,P< 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,P< 0.05) and 4.5-fold higher in late pregnancy compared with postpartum (342 ± 283 versus 76 ± 92 ml/min,P< 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 (rs= 0.68,P< 0.0001). 1-NMN renal clearance increases during pregnancy due to increased glomerular filtration and net secretion by renal transporters.
authors.affiliation: 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.
authors.forename: Mackenzie C
authors.initials: MC
authors.lastname: Bergagnini-Kolev
authors.affiliation: 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.
authors.forename: Mary F
authors.initials: MF
authors.lastname: Hebert
authors.affiliation: 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.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Easterling
authors.affiliation: 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 yvonlin@uw.edu.
authors.forename: Yvonne S
authors.initials: YS
authors.lastname: Lin
mesh_terms: D000328:Adult; D005260:Female; D005865:Gestational Age; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000652:urine; D007668:Kidney / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D008687:Metformin / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000652:urine; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000652:urine; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D000075102:Organic Cation Transporter 2 / Q000378:metabolism; D011247:Pregnancy / Q000097:blood / Q000378:metabolism* / Q000652:urine
chemical_list: D007004:Hypoglycemic Agents; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C521869:SLC47A1 protein, human; C521870:SLC47A2 protein, human; D009536:Niacinamide; D008687:Metformin; C024058:N(1)-methylnicotinamide