System analysis in multiple dose kinetics: evidence for saturable tubular reabsorption of the organic cation N1-methylnicotinamide in humans.
The renal clearance of N1-methylnicotinamide (NMN) was studied in 8 young women at physiological steady state and at steady state following a combined loading bolus and iv infusion. Urinary NMN concentrations were determined using a new HPLC method, plasma levels by a conventional fluorescence method. At physiological levels net tubular secretion of NMN was evident due to a renal fractional excretion, i.e., a ratio of renal NMN clearance to creatinine clearance, above unity. Increasing plasma concentrations lead to an increase in the fractional excretion, indicating saturation of the underlying tubular reabsorption process. Binding to plasma proteins was excluded by ultra-filtration experiments. Clearances measured at physiological levels were about one half of the maximum renal clearance attained following the infusion. This maximum value was approximately six times the creatinine clearance and may be a useful approximation of the renal plasma flow. System analysis, including a novel method to calculate the net response following a multiple input, was used to determine the pharmacokinetic system parameters.
Weber
W
W
Department of Clinical Pharmacology, Klinikum Steglitz, Free University of Berlin, Germany.
Toussaint
S
S
Looby
M
M
Nitz
M
M
Kewitz
H
H
D000042:Absorption; D000328:Adult; D001798:Blood Proteins / Q000378:metabolism; D002412:Cations / Q000378:metabolism / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007668:Kidney / Q000098:blood supply / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D011485:Protein Binding; D012079:Renal Circulation / Q000502:physiology; D013597:Systems Analysis
D001798:Blood Proteins; D002412:Cations; D009536:Niacinamide; C024058:N(1)-methylnicotinamide