Labeled kynurenine pharmacokinetic modeling studies in gerbils. Nonequilibrium between infused and endogenous kynurenine.
In order to complete pharmacokinetic studies on the central vs. peripheral origin of several tryptophan metabolites, we infused gerbils with labelled kynurenine (2H4 or 15N2). Osmotic minipumps charged with kynurenine solutions were surgically implanted subcutaneously in adult female gerbils (50-60 g). After a variable number of hours, the gerbils were sacrificed and organs taken for determination of labelled/unlabelled kynurenine ratios using mass spectrometric assay of a pentafluorobenzyl derivative as described previously. Surprisingly high ratios of 2H to 1H-kynurenine were measured in the kidney (0.25-0.40) and urine (4.0-8.0), although the ratio of deuterium labelled to endogenous kynurenine remained below detection limits (< 0.05) in serum and other tissues. Infusion of greater quantities of 2H4-kynurenine confirmed these observations in gerbils in which ratios of 2H4-to-1H kynurenine were measurable in serum and tissues. Synthesis and infusion of 15N2-kynurenine demonstrated that these effects were not due to deuterium isotope substitution. The data demonstrate a non-equilibrium between infused and endogenous kynurenine, which is related to differential rates of protein binding and the rapid clearance of free, infused kynurenine by kidney.
Kita
T
T
Laboratory of Neurotoxicology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
Heyes
M P
MP
Morrison
P F
PF
Markey
S P
SP
D000818:Animals; D001921:Brain / Q000378:metabolism; D003903:Deuterium; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D005849:Gerbillinae; D007262:Infusions, Intravenous; D007668:Kidney / Q000378:metabolism; D007737:Kynurenine / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D009587:Nitrogen Isotopes; D013997:Time Factors; D014018:Tissue Distribution
D009587:Nitrogen Isotopes; D007737:Kynurenine; D003903:Deuterium