THE PHARMACOKINETICS OF PYRIDOSTIGMINE AND 3‐HYDROXY‐N‐METHYLPYRIDINIUM IN THE RAT: DOSE‐DEPENDENT EFFECTS AFTER PORTAL VEIN ADMINISTRATION

1 The elimination kinetics of [14C]‐pyridostigmine iodide and [14C‐methyl]‐3‐hydroxypyridinium bromide (3‐OH NMP) have been studied in the rat. 2 For pyridostigmine, at a given dose level, the fraction of the dose eliminated unchanged was reduced and the metabolite fraction was increased after portal vein administration when compared to jugular vein administration. This indicates that pyridostigmine is subject to metabolism during the first passage through the liver. 3 When doses of pyridostigmine 1.25 μmol/kg and higher were injected via the portal vein, the proportion excreted in urine as unchanged drug remained constant; in contrast, the percentage of the dose eliminated as the metabolite was significantly reduced. This indicates that a dose‐dependent process is involved in the urinary excretion of 3‐OH NMP. 4 This conclusion was supported by studies involving the portal and systemic venous injection of 3‐OH NMP at different dose levels. After 4 h, approximately 85% of the lowest dose was eliminated unchanged in urine; in contrast, only 63% of the higher dose was excreted during this period. The proportion of the dose eliminated in urine was not related to the route of administration. 5 After the injection of pyridostigmine into the jugular vein, the initial rate of drug excretion fell rapidly for approximately 10 min; in contrast, after injection into the portal vein, the rate of excretion of the drug rose to a maximum at 30 minutes. This suggests that the hepatoportal system behaves as a distinct region during the distribution of this drug.